Handbook of Clinical Gender Medicine
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448 pages

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Gender medicine is an important new field in health and disease. It is derived from top-quality research and encompasses the biological and social determinants that underlie the susceptibility to disease and its consequences. In the future, consideration of the role of gender will undoubtedly become an integral feature of all research and clinical care. Defining the role of gender in medicine requires a broad perspective on biology and diverse skills in biomedical and social sciences. When these scientific disciplines come together, a revolution in medical care is in the making. Covering twelve different areas of medicine, the practical and useful Handbook of Clinical Gender Medicine provides up-to-date information on the role of gender in the clinical presentation, diagnosis, and management of a wide range of common diseases.



Publié par
Date de parution 17 août 2012
Nombre de lectures 0
EAN13 9783805599306
Langue English
Poids de l'ouvrage 3 Mo

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Handbook of Clinical Gender Medicine
Handbook of Clinical Gender Medicine
Karin Schenck-Gustafsson     Stockholm
Paula R. DeCola     New York, N.Y.
Donald W. Pfaff     New York, N.Y.
David S. Pisetsky     Durham, N.C.
62 figures, 4 in color, and 63 tables, 2012
To our present and future children and grandchildren.
Karin Schenck-Gustafsson, MD, PhD, FESC Center for Gender Medicine Cardiac Unit, Department of Medicine Karolinska University Hospital Solna Karolinska Institutet Stockholm, Sweden
Paula R. DeCola, RN, MSc Pfizer Inc. New York, N.Y., USA
Donald W. Pfaff, PhD Department of Neurobiology and Behavior The Rockefeller University New York, N.Y., USA
David S. Pisetsky, MD, PhD Division of Rheumatology and Immunology Department of Medicine Duke University Medical Center Medical Research Service, Durham VA Hospital Durham, N.C., USA
Library of Congress Cataloging-in-Publication Data
Handbook of clinical gender medicine / editors, Karin Schenck-Gustafsson.… [et al.]. p.; cm.
Includes bibliographical references and indexes.
ISBN 978-3-8055-9929-0 (hard cover: alk. paper) – ISBN 978-3-8055-9930-6 (e-ISBN) I. Schenck-Gustafsson, Karin.
[DNLM: 1. Clinical Medicine - - methods. 2. Sex Factors. 3. Socioeconomic Factors. QZ 53]
Bibliographic Indices. This publication is listed in bibliographic services.
Disclaimer. The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
© Copyright 2012 by S. Karger AG, P.O. Box, CH-4009 Basel (Switzerland)
Printed in Germany on acid-free and non-aging paper (ISO 9706) by Bosch Druck, Ergolding
ISBN 978-3-8055-9929-0
e-ISBN 978-3-8055-9930-6
Wainer, J. (Clayton, Vic./Box Hill, Vic.); Wainer, Z. (Melbourne, Vic.)
Schenck-Gustafsson, K. (Stockholm)
Gender Matters
Wainer, J. (Clayton, Vic./Box Hill, Vic.); Wainer, Z. (Melbourne, Vic.)
Biological Sex and the Genome: What Makes Us Ourselves?
Legato, M.J. (New York, N.Y.)
Social and Biological Determinants in Health and Disease
Section Editors: DeCola, P.R. (New York, N.Y.); Schober, J.M. (Erie, Pa.)
Gender Effects on Health and Healthcare
DeCola, P.R. (New York, N.Y.)
A Global War against Baby Girls: Sex-Selective Abortion Becomes a Worldwide Practice
Eberstadt, N.N. (Washington, D.C.)
Fetal Programming
Glezerman, M. (Petah Tiqwa/Tel Aviv)
Ambiguous Genitalia
Mouriquand, P.D.E. (Bron); Schober, J.M. (Erie, Pa.)
Central Nervous System and Clinical Applications
Section Editor: Pfaff, D.W. (New York, N.Y.)
Chronic Stress and Allostatic Load
Juster, R.-P.; Lupien, S.J. (Montreal, Que.)
Knickmeyer, R. (Chapel Hill, N.C.); Baron-Cohen, S. (Cambridge)
Rubinow, D.R.; Craft, C.D. (Chapel Hill, N.C.)
Violence: Adaptive Regulated Aggression Contrasted with Violence Against Women
Kreinin, T. (Washington, D.C.); Esteva, C.G.M. (Geneva); Pfaff, D.W. (New York, N.Y.);
Lusweti, S.; Shauri, H.S. (Kilifi)
Section Editor: Olsson, T. (Stockholm)
Parkinson’s Disease
af Edholm, K.; Svenningsson, P. (Stockholm)
von Euler, M. (Stockholm)
Multiple Sclerosis
Olsson, T. (Stockholm)
Tomson, T.; Sveinsson, O. (Stockholm)
Migraine and Other Headaches
Waldenlind, E. (Stockholm)
Section Editor: Murphy, A.Z. (Atlanta, Ga.)
Kosek, E. (Stockholm)
Temporomandibular Joint Disorders
Lim, P.F.; Maixner, W.; Khan, A.A. (Chapel Hill, N.C.)
Irritable Bowel Syndrome
Kilpatrick, L.A.; Tillisch, K. (Los Angeles, Calif.)
Pain and Analgesia
Loyd, D.R. (Fort Sam Houston, Tex.); Murphy, A.Z. (Atlanta, Ga.)
Section Editor: Schenck-Gustafsson, K. (Stockholm)
Coronary Heart Disease
Schenck-Gustafsson, K. (Stockholm)
Coronary Heart Disease and Female Sex Hormones
Schenck-Gustafsson, K. (Stockholm)
Heart Failure
Kühn Madsen, B. (Holbaek)
Insulander, P.; Vallin, H. (Stockholm)
Section Editor: Gustafsson, J.-Å. (Houston, Tex./Stockholm)
Ernberg, I. (Stockholm)
Three Nuclear Receptors Involved in Gender-Related Proliferative Diseases (ER-β, LXR-α, and LXR-β)
Warner, M. (Houston, Tex.); Gustafsson, J.-Å. (Houston, Tex./Stockholm)
Metabolic Disease
Section Editor: Werner, S. (Stockholm)
Type 1 Diabetes
Ma, R.C.W.; Chan, J.C.N. (Hong Kong SAR)
Type 2 Diabetes
Chamnan, P. (Cambridge/Hong Kong SAR); Ma, R.C.W.; Chan, J.C.N. (Hong Kong SAR)
Rössner, S.M.; Rössner, S. (Stockholm)
Pituitary and Thyroid Diseases
Werner, S. (Stockholm)
Diseases of Calcium Metabolism and Bone Metabolic Disorders
Thorén, M. (Stockholm)
Adrenal Disorders, Female Androgen Deficiency, Hirsutism, and Endocrine Hypertension
Thorén, M. (Stockholm)
Dhejne, C.; Arver, S. (Stockholm)
Autoimmune, Inflammatory, and Musculoskeletal Disease
Section Editor: Pisetsky, D.S. (Durham, N.C.)
Systemic Lupus Erythematosus
Shiraishi, M.; Clowse, M. (Durham, N.C.)
Rheumatoid Arthritis
Lesuis, N. (Nijmegen); van Vollenhoven, R.F. (Stockholm)
Sowers, M.; Karvonen-Gutierrez, C.A. (Ann Arbor, Mich.)
Eder, L.; Gladman, D.D. (Toronto, Ont.)
Hershfield, M.S. (Durham, N.C.)
Infectious Diseases
Section Editor: Britton, S. (Stockholm)
HIV Infection
Tozzi, V. (Rome)
Färnert, A.; Kulane, A. (Stockholm)
Measles Infection
Aaby, P. (Bissau Codex)
Ekéus Thorson, A. (Stockholm)
Urology, Sexual Dysfunction, and Nephrology
Section Editor: Arver, S. (Stockholm)
Lower Urinary Tract Symptoms, Benign Prostatic Hyperplasia, and Overactive Bladder
Peeker, R. (Gothenburg)
Sexual Dysfunction in Women
öberg, K. (Stockholm)
Sexual Dysfunction in Men
Buvat, J. (Lille)
Chronic Kidney Disease
Carrero, J.-J. (Stockholm)
Pharmaceutical Drugs
Section Editor: Parekh, A. (Silver Spring, Md.)
Women in Clinical Drug Trials: United States Food and Drug Administration Update on Policies and Practices
Parekh, A. (Silver Spring, Md.)
Drug Disposition and Effect
Mattison Faye, A.C. (Columbia, S.C.); Mattison, D.R. (Bethesda, Md./Ottawa, Ont.)
Section Editor: Herlitz, A. (Stockholm)
Aging in a Gendered Society: Social and Biological Determinants of Health in the Elderly Population
Parker, M.G. (Stockholm)
Mangialasche, F.; Marengoni, A.; Kivipelto, M. (Stockholm)
Wang, H.-X.; Kivipelto, M. (Stockholm)
Herlitz, A.; Lovén, J. (Stockholm)
Author Index
Subject Index
No one should be sick or die because of gender inequality
The World Health Organization Department of Gender, Women, and Health
The authors you will read in the Handbook of Clinical Gender Medicine have responded to the intriguing challenge of describing their discipline through the lens of both gender and sex differences. Grappling with sex and gender requires skills in both the biomedical and social sciences, and when those two thought systems come together, a revolution is in the making. The Handbook of Clinical Gender Medicine addresses this challenge across twelve body systems, providing evidence about the implications of gender and sex in relation to presentation, diagnosis, and treatment of disease processes. It is both practical and useful, as a textbook should be.
The authors who have contributed to the Handbook of Clinical and Gender Medicine have explained how sex and gender affects medical understanding of pain, epilepsy, violence, metabolic bone disorders, heart disease, and malaria, among other conditions. This is a medical textbook that is both the same as the leading texts that resource clinical practice and yet profoundly different. The promise is that once you have read this textbook you will understand your branch of medicine with new vision for the rest of your life as a clinician.
All of us, scientists, doctors, and patients, can be grateful for the contributions of the pioneering authors in this textbook. We encourage you to enjoy the insights that their use of the gender lens generates in their respective disciplines and to apply it to your own work in patient care. It is a joy to read this foundational text on the emerging field of gender and medicine.

Jo Wainer , Clayton, Vic./Box Hill, Vic., Australia
Zoe Wainer , Melbourne, Vic., Australia
The idea for this book came to me gradually during the first years of the new millennium after we had opened the Center for Gender Medicine at Karolinska Institutet, in Stockholm, Sweden, in 2001. At our 3rd International Congress of Gender Medicine in Stockholm in 2008, we had a preliminary book meeting and many colleagues seemed interested in the project. At about the same time, the Center obtained funding from Pfizer Inc. to support the development of this book.
An executive committee was formed and its members consist of, besides me (Prof. Karin Schenck-Gustafsson, Karolinska Institutet, Stockholm): Paula R. De Cola, RN, MSc, Pfizer, New York, N.Y., USA; Prof. David S. Pisetsky, Duke University, Durham, N.C., USA, and Prof. Donald W. Pfaff, Rockefeller University, New York, N.Y., USA. The journalist Tina Esh, BSc, Tina Esh Communications AB, Stockholm, is the book coordinator.
We first had to decide on the content of the book. High priority was that it should serve as a guide for clinical work. Therefore, most chapters are very clinical while a few are more theoretical or philosophical, depending on the nature of the topic.
The chapters should contain statements about the actual status of knowledge as well as comments about missing facts. We hope that this book will inspire others and lead to more research, more work on clinical guidelines, and more advocacy for gender medicine considerations among groups such as health authorities, ethics committees, editorial boards, research councils, medical product agencies, and biopharmaceutical companies.
It was a long struggle to find a publisher that understood our intentions and shared the beliefs that gender medicine is both for men and women, includes both biological and social aspects of health and disease, is based on top-quality research, and in the future will be a natural part of all research and clinical work. I also believe that our authorities should demand that all medical research include both sexes, show sex-divided statistics, and always analyze results from a sex and gender perspective.
We have engaged authors that are top researchers and top clinicians from Europe, the USA, Canada, Africa, China, and Australia who share my passion for the heightened prominence of gender medicine, and I believe that we have an outstanding book that will contribute to this goal.
Enjoy the reading!

Karin Schenck-Gustafsson , Stockholm
Schenck-Gustafsson K, DeCola PR, Pfaff DW, Pisetsky DS (eds): Handbook of Clinical Gender Medicine. Basel, Karger, 2012, pp 1–4
Gender Matters
Jo Wainer a , b Zoe Wainer c
a Eastern Health Clinical School, Faculty of Medicine, Nursing and Health Sciences, Monash University, Clayton, Vic., b Eastern Health, Box Hill, Vic., and c Department of Surgery, St. Vincent’s Hospital, The University of Melbourne, Melbourne, Vic., Australia
Sex and gender are both critical variables that affect health and illness. Gender is a social science descriptor and sex is a biological one. Gender and possibly sex are not binary variables.That we think of them as such is a political decision rather than a description of the natural world. It may be scientifically more accurate to treat them as continuous variables for the purposes of research. Wherever possible, scientific research will benefit from treating men and women as separate populations, or modeling sex and gender as continuous variables. It is time to move on from the foundation built on the European male as the model human. The dominance of this model is a result of a fierce battle between competing world views over thousands of years. The masculine perspective won that battle, as recorded in the myths and legends of Europe and other cultures. In the process, the feminine was suppressed, women became invisible, and their contributions to the creation of knowledge disappeared. The rule of the fathers brought with it a binary foundation to thinking and the preeminence of rational thought. Feelings, intuition, and nature were abhorred. Nature was a force to be conquered. Distrust of the feminine has been deeply embedded in the development of the science on which medicine is based, with important consequences that are considered by the authors of this textbook. No problem can be solved from the consciousness that created it. It is time to combine the biological and social sciences to unleash a revolution in scientific thought appropriate for the 21st century.
Copyright © 2012 S. Karger AG, Basel
In the age of personalized medicine that seeks to apply targeted individualized therapy, we seem to have missed two of the most overt genotypes and phenotypes that patients present with: those of sex and gender. Personalized medicine requires understanding the impact of the X and Y chromosomes on the molecular profile of women and men, and the health effects of gender roles ascribed to men and women and those with other gender identities.
Western science is now ready to move through the gateway from medical science built on the foundations of reductionist linear thinking that defined all patients in relation to the 70-kg European male, to an expansive capability that includes in scientific understanding of disease and medical care the complexity of the whole person that is the patient.
An example of the importance of identifying the impact of gender and sex can be seen in prostate cancer and lung disease. When masculinity is defined through the qualities of a warrior it is difficult to admit to weakness or to seek care. The resulting delay in responding to symptoms leads to worse outcomes in prostate disease that are a result of gender, not changes in testosterone. In women, the increasing incidence of lung cancer began when it became acceptable for women to smoke, a change in gender rules, not estrogen. It has become apparent that women with lung cancer live longer than men, even when known prognostic factors are controlled for. This is a survival outcome determined by sex, and the research design required to explore this must test the data on women and men separately.
To understand the importance of this textbook in the development of biomedical thought, it is necessary to grasp the essential elements of how things got to be the way they are. We are at a point of transition in the history of thought in the Western tradition. The transition is from 3,000 years in which humans have refined intellectual thought through the use of reason and the order of the father right, to a new point in which the feminine is re-emerging and with it expanded ways of knowing. The consequences are being felt in all spheres of human activity, including in the construction of scientific thought and medicine.
The stories about how things came to be the way they are are told in myths and legends, and we would do well to know what they are, for myths set the tone for a whole society. European myths tell how the feminine was defeated in epic battles between the goddesses and the gods. The gods won, and from that time on men as their representatives on earth took on the roles of leadership, politics, war, and knowledge making. In the process, the feminine was ruthlessly suppressed and women became invisible, their contributions to the creation of knowledge erased from public consciousness.
The mythical defeat of the feminine has its parallel in the real world. One of the most savage ways it manifested in Europe was through the Inquisition, a systematic attack on women and the feminine that at some points particularly targeted women who were healers and named them as witches.
Witches lost their central place in theorizing during the 18th century, when natural philosophy was radically reconstituted. Natural theology (which required divine intervention in the order of things) was replaced by rational theology in which God was held to be omniscient and prescient rather than interventionist in a daily sense. With rational theology came rational science, a science based on observation and an understanding of the ordered nature of nature, a ‘mechanical’ view of nature that has prevailed since. The witch burnings, then, could be considered part of the process of science cleansing itself of magic, part of the triumph of mechanistic thinking ushered in by Descartes. The witch burnings were the backdrop to the fierce competition among medical paradigms - Galenist, Paracelsian, iatrochemical, mechanistic - that was part of the scientific revolution of the early modern age.
Rational thought became the science on which modern medicine is based, and it contains within it a horror of magic, nature, chaos, intuition, and the feminine. The medical profession was developed in part to distinguish itself from the activities of others who claimed to heal, at a time when women and the feminine had been tortured into silence. That modern science, and with it modern medicine, were deeply implicated in the reification of the masculine, and rose from the ashes of the witches’ pyre, makes the relationship between the feminine and medicine highly problematic. Distrust and fear of the feminine remains deeply embedded in medicine as an inadequately identified legacy with hidden consequences that this book’s authors are opening to scrutiny. It is essential to come to grips with this engendering of medical knowledge if we are to understand how gender and medicine interact.
Gender, of course, includes all sexes and sexual identities and is not code for women; however women are the missing majority. This is the right time to grapple with the idea that gender, and possibly sex, are not binary phenomena and that they are described as such in scientific literature as the result of acts of power that have made sexual and gender variability sources of hostility and invisibility. The need to ensure that sex is dichotomous is not universal, and many Asian and traditional cultures have spaces for people who identify as neither exclusively female nor male. Sex and gender may be better considered as a fluid continuum along which people can position themselves variously during their lives.
In one Australian Indigenous culture, boys and girls can choose their gender roles and change them during their lifetime, and there is no such thing as sexual ambiguity because you are who you are. This is a radically transformative thought. It has the power to break apart the dichotomous thinking that underpins the power systems that are in place now. The work of gender and medicine has this power to transform science and clinical care.
The philosophy of Plato that created dichotomous thought was the means by which Western systems created binary categories to help order a disordered universe, including male and female. These categories extended beyond the sexual divide to include foundational concepts such as good and bad, mind and emotion, science and nature, knowledge and opinion, and soul and body. The technical consequences of dualism are the science and digital revolution we are living through today. The political consequences were that all of the good, mind, science, knowledge, and soul categories were joined together in a slippery move that aligned them with male and left female embedded within all that was unknowable and mysterious.
The Christian Bible then compounded the divide by commanding man to have dominion over all other living things, including women and nature and ‘every creeping thing’. If we are to survive as a species, this dualistic and power-over thinking must change. Now that we know that we have to do things differently, the obvious place to begin is by embracing what men and women have to offer collaboratively and unpacking the ways of the feminine with reverence instead of horror.
What can we know when we include the feminine? Einstein wrote that no problem can be solved from the same level of consciousness that created it. The possibilities that have been held in the unconscious for thousands of years are re-emerging in the science of gender and medicine.
One example is the exciting concept of biomimicry, which takes inspiration from nature to solve human problems. It is based on the realization that instead of dominion over nature we need to understand her if we are to survive as a species. Nature has been problem-solving for billions of years, and every life form in existence today is the product of those billions of years of experimental research. It is an example of the power of paradigm shifts in thinking, one that coincides with the emergence of the feminine.
It has taken thousands of years to create the thought systems that we know now. It will take just decades to build on this accumulated wisdom with the new tools that come with understanding the clinical implications of sex and gender. That is the work that is described in this textbook. Within a decade, the scientists and clinicians of the Western world will ask, ‘how could we have missed that?’.
In their rigorous pursuit of knowledge, scientists and doctors will join with social scientists to gain the benefits of hybrid vigor. Gender is a concept of the social sciences and it takes the epistemologies and methodologies of the social sciences to unpick the meaning to improve clinical care. The creative insights that are released when the two thought forms are employed together will astound with their discoveries.
Jo Wainer, AM, PhD Eastern Health Clinical School Faculty of Medicine, Nursing and Health Sciences Monash University Wellington Road Clayton, VIC 3800 (Australia) Tel. +61 3 9094 9573, E-Mail jo.wainer@monash.edu
Schenck-Gustafsson K, DeCola PR, Pfaff DW, Pisetsky DS (eds): Handbook of Clinical Gender Medicine. Basel, Karger, 2012, pp 5–7
Biological Sex and the Genome: What Makes Us Ourselves?
Marianne J. Legato
Partnership for Gender-Specific Medicine, Columbia University, New York, N.Y., USA
The last three decades have witnessed a revolution in our concept of the importance of biological sex in determining phenotype. More and more we are successfully meeting the challenge of studying females directly at all levels of research rather than making males normative for the entire population. As a consequence, we have discovered fascinating and completely unanticipated differences between the sexes.Those differences exist not only at the macroscopic level and in the organism as a whole, but also at the molecular level: for example, we now know that the same genes are expressed differently as a function of gender. Gender-specific biomedical investigation has helped us formulate questions about normal function and the pathophysiology of disease we never would have otherwise asked and has deeply enriched and expanded our notion of precisely what makes us ourselves.
Copyright © 2012 S. Karger AG, Basel
Heraclitus, the philosopher of change, pointed out that the only thing of which we can be completely certain is that everything in the world around us is in flux and that nothing endures but change itself [ 1 ]. Medical science and medical opinions are no exception: as scientific data accumulate, we construct theories and formulate paradigms that we inevitably and constantly alter. The evolution of the concept of ‘gender-specific medicine’ is a classic example of that principle.
The notion that all human biology, with the exception of that of our reproductive systems, is essentially the same for men and women dominated medicine for centuries. In fact, the idea that what we know about males cannot be extrapolated to females without direct testing of female subjects is less than 25 years old. Suggesting that what we found in males might only be true of one sex and could not be extrapolated without separate testing in females met with tremendous skepticism and even outright opposition. In fact, it is astounding to think that centers of medical research tolerated and indeed promulgated the idea that sex was not a significant determinant of normal function and of the experience of disease.
Thus, scientists themselves are imperfect; they do not spring fully and perfectly formed like Athena from the brow of Zeus: one’s style in shaping a method of scientific inquiry is not wholly objective: basic talent, the caliber of training, and, importantly, prejudices, all influence investigative style and substance. A whole variety of other factors impact medical investigation. Public interest is one: money drives the research engine, and the public is the source of that money and the ultimate arbiter of what it will pay for. The prevailing wisdom of the research community dictated that to repeat research protocols that had been completed in men to women seemed an unnecessary waste of funds. History is another factor: it shapes attitudes in medicine as in all sections of society. After the abuses of World War II were exposed to general scrutiny at Nuremberg, a determination to protect the more vulnerable members of society from exploitation under the guise of furthering medical knowledge was forged and dominated the American research enterprise for decades. Women, particularly premenopausal women, were considered more vulnerable than men and shielded accordingly from sharing the risk of being subjects of clinical investigation. This attitude was, however, countered by the effective lobbying of the feminist community (itself a direct result of the experience of the war), which petitioned the government to support the direct investigation of women’s physiology.
The Task Force on Women’s Health, sponsored by Dr. Edward Brandt at the Public Health Department, spearheaded an effort by the National Institutes of Health and the Congress itself to fund and support direct research on women. The Office of Research of the NIH, headed by Doctor Vivian Pinn, played a major role in guiding and shaping efforts to comply with that mandate. In the decade that followed, a dedicated coalition of feminists, physicians, and medical researchers stabilized and expanded the idea that women were significantly different from men and profited from a direct investigation of their physiology and their experience of disease. The rich bonanza of data that resulted, however, was completely unanticipated: to our growing amazement, we found that every system of the body was different in significant ways between males and females. The differences extended to the molecular level: thousands of identical genes are expressed differently in males and females [ 2 ]. Furthermore, gene expression is modified by the parent of origin in the process called imprinting and, even more significantly, the loci and number of parentally imprinted genes vary with the sex of the offspring. The impact of sex on the genome is far more extensive than was ever anticipated [ 3 , 4 ].
Another revolution in our concept of gender-specific medicine was the old debate of whether our sex-specific differences are cast in biological stone or rather our environment is in fact more important in shaping the phenotype. Many have speculated that if men and women were subjected to environments that were utterly identical, sex-specific biology would disappear. This extreme view is a distortion of what is, in fact, correct: experience plays a direct and essential role in altering biological properties and cannot be ignored or separated out from what it means to be male or female. The intricate dance between our DNA, experience/environment, hormones, and developmental age is a composite of inextricably intertwined events, all of which produce the ultimate version of our phenotype. Biological sex and gender are not two separate concepts, but follow a final common path; ‘gender-specific medicine’ is a unifying term that includes and takes into account all the contributing factors that produce the functioning organism.
There are many more miles to go before we fill in the blank spots in our understanding of gender-specific science. Three members of the faculty of the Department of Obstetrics and Gynecology at the Feinberg School of Medicine at Northwestern University pointed out in a recent editorial in Nature that women still remain underrepresented in biomedical research [ 5 ]. They referred to a 2004 study surveying nine important medical journals that showed only 37% of the participants were women and only 13% of the studies analyzed data by sex [ 6 ]. It is not enough, however, to agitate for more carefully balanced investigation: women themselves must acknowledge their duty to participate wherever possible in clinical research as a matter of justice; men should not have to bear the burden of the risks involved alone.
We should be striving to give full weight to all the ingredients that determine our gender-specific function throughout our lives: from the moment of conception to our death we are the product of our biological sex, our hormones, and the impact of our environment and experiences on the very stuff and substance of which we are made. The human genome is not, as some have already pointed out, the Holy Grail, which when decoded will give us a complete understanding of each person’s unique phenotype. A fuller and more accurate understanding of who we are and how we became this way depends on a balanced view of all the components that operate throughout the lives of all of us to produce who and what we are.
1 Heraclitus of Ephesus (ca. 535-475 BC) quoted by Plato in: Cratylus, and by Diogenes Laertius in: Lives of the Philosophers Book IX, section 8. http://en.wikiquote.org/wiki/Heraclitus .
2 Yang X, Schadt Wang S, Wang H, Arnold AP, Ingram-Drake L, et al: Tissue-specific expression and regulation of sexually dimorphic genes in mice. Genome Res 2006;16:995–1004.
3 Gregg C, Zhang J, Butler JE, Haig D, Dulac D: Sex-specific parent-of-origin allelic expression in the mouse brain. Science 2010;329:682–685.
4 Gregg C: Parental control over the brain. Science 2010;330:770–771.
5 Kim Alison M, Tingen Candace M, Woodruff Teresa K: Nature 2010;465:688–689.
6 Geller SE, Adams MG, Carnes MJ: Womens Health 2006;15:1123–1131.
Marianne J. Legato, MD Partnership for Gender-Specific Medicine, Columbia University 903 Park Avenue, Suite 2A New York, NY 10075 (USA) Tel. +1 212 737 5663, E-Mail mjl2@columbia.edu
Social and Biological Determinants in Health and Disease
Section Editors

Paula R. DeCola, RN, MSc
Justine M. Schober, MD, FAAP
Pfizer Inc.
Department of Urology
New York, N.Y., USA
UPMC Hamot

Erie, Pa., USA
Social and Biological Determinants in Health and Disease
Schenck-Gustafsson K, DeCola PR, Pfaff DW, Pisetsky DS (eds): Handbook of Clinical Gender Medicine. Basel, Karger, 2012, pp 10–17
Gender Effects on Health and Healthcare
Paula R. DeCola
Pfizer Inc., New York, N.Y., USA
With the advent of gender medicine there is the recognition that differences exist between and among men and women in relation to their health due to the interplay of biologically determined and socially derived elements. This has an impact on preventive, curative, and rehabilitative aspects of health and most body systems. The intent is to explore gender-based differences as well as disparities and their effect on health and health care.
Copyright © 2012 S. Karger AG, Basel
Defining Terms and Measurement
Gender-based medicine encompasses sex differences (genetic, biological, and phenotypic) but goes beyond these to include the broader social, cultural, and normative factors that affect health. Its roots are partly embedded in the women’s health movement of the 1970s, since through the recognition of women’s health came the acknowledgement of gender differences. However, gender medicine is not women’s health and it is it not binary. It extends past the health of women to create new prototypes of male health, as well as to encompass the biological and social aspects of lesbian, gay, bisexual, transgender, and intersex (LGBT) people.
As with gender medicine, the working definition of disparities extends past a simple one that only accounts for an identified difference between two groups to subsume the idea of social justice. The term is used in keeping with the World Health Organization’s perspective that notes that disparities include a difference between two groups that is viewed as being unfair and unjust, as well as being both unnecessary and avoidable. Further, when determining disparities, equity and not equality needs to be considered through the assessment of need as well as of outcomes, since equal treatment may in fact perpetuate a disparity.
The Research Void
As noted by Marianne Legato, a leader in gender medicine, women are not little men, and all men are not alike. In fact, there is growing recognition that biomedical and clinical research has focused on males as a relatively heterogonous group. It has, in large measure, ignored women with the exception of reproduction, ignored LGBT populations with the exception of sexually transmitted diseases, and ignored other minorities and largely concentrated research efforts within high-income countries.
In the 1990s, in response to the paucity of research on women, a number of jurisdictions established requirements that sex be considered in study designs in order for grant requests to be eligible for governmental funding. Requirements along these lines can be found in diverse counties such as the USA, South Africa, and Australia. However, no requirement or incentive exists that promotes research for other key groups such as LGBT populations or that requires sex and gender to be considered in the composition of ethic committees or in the review of research proposals. This oversight points to a potential root cause for certain health disparities that undoubtedly have health and healthcare system equity implications.
Healthcare Utilization
Across the healthcare landscape we see different utilization rates, as well as different barriers and enablers to healthcare access. For example, women in high-income countries are more likely to engage in preventative health activities than are men. They are also more likely to seek treatment for most diseases and to do so early in the course of an illness [ 1 ]. In contrast, women within emerging economies, such as those of Ghana and India, have been shown to utilize health systems less than men during their lifespan due to restrictive barriers such as childcare duties and care giving obligations, as well as service cost [ 2 , 3 ]. Irrespective of country of origin, women in general are less likely to perceive their overall cardiac risk level and therefore are less likely to attribute their symptoms to a possible cardiac related health issue [ 4 ].
Men’s lower healthcare utilization rates in high-income countries are linked to the trend that they are fulltime workers, work longer hours, and have less flexible schedules than women do [ 1 , 5 ]. Additionally, the presence of long wait times (more than 1 week) for a routine care appointment is a strong negative predictor of men accessing the health system within the USA [ 1 ]. Although variation may exist across countries, a study conducted in Denmark shows that working-age men have higher rates of hospitalization and mortality than their female counterparts [ 6 ]. This is attributed to lower rates of healthcare practitioner contact [ 6 ].
Available information from both the USA and Canada provides insights with respect to the LGBT population’s utilization of healthcare systems. Lesbians and gay men are less likely to seek preventive care, such as cancer-screening services, and to have poorer health maintenance behaviors than the general population [ 1 , 7 , 8 ]. This disparity is thought to be attributable to stigma, healthcare professionals’ perceived biases, lack of clinical and cultural knowledge, and lack of gender-sensitive care [ 1 , 7 , 8 ].
Lesbians are also less likely to have health insurance, to see a healthcare practitioner, or to have a consistent source of care [ 1 , 7 , 8 ]. This population is believed to underutilize health systems and delay health seeking [ 1 , 7 , 8 ]. In contrast, gay men living with a partner are as likely as a male living with a female partner to have a consistent source of care and to have significantly elevated chances of having seen a clinician within the last year [ 1 , 7 ].
Transgender, bisexual, and intersex people are less likely to utilize the healthcare system than is the population as a whole [ 7 , 8 ], while research demonstrates that trans-gender people are less likely to be insured than the general population. The underutilization of the healthcare system by bisexuals and intersex people is reported as being due to their perception that healthcare professionals lack the requisite knowledge to support their unique needs [ 7 , 8 ].
The Morbidity and Mortality Paradox
When we look at health status in terms of mortality rates, we see that men’s life expectancy at all ages is less than that of women in most countries around the world (on average around 6-8 years less). This mortality gap is wider in the former Soviet Union countries. In fact, Russia reached an unprecedented 13-year difference between male and female life expectancies in the 1990s; this is primarily attributed to high rates of circulatory disease among the men [ 9 ]. Meanwhile, in the USA and other high-income countries the gap is narrowing. The US 2010 census shows that the gender mortality gap is getting smaller, most significantly in the above 65 year range.
In general, the shorter life expectancy in men is thought to be the result of male behaviors including greater risk taking in relation to tobacco and alcohol use [ 1 , 10 ]. It is also attributed to masculine attitudes towards health, such as not expressing pain or discomfort or acknowledging emotions [ 1 , 10 ]. In some low-and middle-income countries in Asia, a deviation from this trend is seen; women’s life expectancy at birth is actually lower than or equal to men’s [ 11 ]. This is thought to be due to socially mediated causes including maternal mortality, disparities in access to care, female infanticide, and lack of female empowerment [ 11 ]. It is worth noting that, irrespective of the gender mortality trends, about 350,000 women die each year, predominantly in low-and middle-income countries, due to pregnancy and childbirth. Neither of these conditions in isolation constitutes an illness or disorder.
While men in most instances are more likely to die earlier than women, epidemiological information points to greater morbidity in women, based on rates of self-reporting and provider reporting [ 1 , 12 ]. This finding is further supported by research in the USA that reveals that on a per capita basis women’s spending on health care services exceeds that of males [ 13 ]. Another study provides additional cultural insights in that women in Canada were shown to be more likely than men to report unmet health needs; this is within a country that provides universal basic care [ 14 ]. Women’s spending rates and their likelihood to report unmet health needs may be either a consequence of or a causative factor in the higher rates of morbidity in women.
Although the medical literature overwhelmingly points to a gender difference, there has been some questioning of the existence and the extent of any gender difference in morbidity. It has been proposed that when lifespan and disease area variation is accounted for, any noted difference in morbidity rates is attenuated [ 1 ]. Others reports suggest that the variation is an artifact due to factors such as higher rates of hospitalization due to childbirth in women, women’s increased tendency toward seeking out health services resulting in higher diagnosis rates as well as higher rates of medication usage, and women’s greater inclination to identify complaints believed to be health related [ 1 ].
Morbidity in Lesbian, Bisexual, Gay, Transgender, and Intersex Populations
Disparities within LGBT populations as well as differences among them exist in relation to disease patterns and behaviors affecting health. A consistent disparity across LGBT populations is that they are at a higher risk for violence than the general population, with one third to one fourth of this population in the USA having experienced a violent act. Mental health is also an area of special concern, notably depression and anxiety [ 7 , 8 ]. LGBT people are more than four times as likely to have attempted suicide as the general US population. Eating and body image disorders have a higher prevalence in gay and bisexual men compared to their heterosexual peers [ 7 , 8 ]. It is believed that all of these mental health conditions are manifested as the result of being marginalized within society, coupled with a history of emotional or physical abuse [ 7 , 8 ].
Additionally, higher rates of recreational drug use among gay men, higher rates of obesity among lesbians, and overall higher rates of tobacco use in LGBT populations have been reported in the USA and Canada and may result in increased morbidity [ 7 , 8 ]. The use of tobacco puts this population at a higher risk for lung cancer and chronic obstructive pulmonary disease, obesity increases the risk of a number of non-communicable diseases, and finally recreational drug use can lead to an increased risk of sexually transmitted diseases due to an increase in high-risk sexual behaviors [ 7 ].
When we look at other areas of increased disease prevalence we see that lesbians are at a greater risk for morbidity and mortality due to gynecological cancers, especially ovarian cancers [ 7 , 8 ]. This risk is thought to be compounded by the tendency to delay routine healthcare [ 7 , 8 ]. Higher cancer risk is also seen in men who have sex with men. They have a higher prevalence of anal human papilloma virus which can result in anal cancer [ 7 , 8 ].
There is little research on transgender morbidity but, due to exposure to hormone therapy over extended periods of time, transgender people may be at increased risk of hormone-related cancers [ 7 , 8 ]. Special concern also exists regarding the self-administration of high-dose hormone regimens, without medical supervision, within the transgender population [ 15 ]. This practice poses an obvious and significant health risk.
Healthy aging is a shared goal between sexes and across the gender continuum, yet as the numbers of aging people grow, our knowledge on the topic does not keep pace and our health systems remain largely focused on curative rather than preventive care.
Interestingly, in some high-income countries the higher rates of morbidity in women compared to men are either somewhat diminished or absent as women age [ 1 ]. In contrast, a study within India demonstrated that women over the age of 60 continue to report a higher prevalence of disabilities, worse self-rated health, and marginally lower chronic conditions compared to same-aged men [ 3 ]. However, when controlled for a number of socioeconomic conditions, the study shows that financially empowered women have equal or better health than similarly aged men [ 3 ]. Another study conducted in Africa and Asia shows conflicting information in that women have significantly worse self-reported health than do men even when differences in demographic and socioeconomic factors are adjusted for [ 16 ]. These last findings are of particular interest since the majority of women 60 years of age or older reside in low-and middle-income countries and the overall proportion of older people within these countries is rising [ 11 ].
In light of LGBT populations’ tendency toward having delayed, avoided, or been the recipient of mismanaged care over their lifespan, they are at a greater risk for increased health issues as they age. They are also disadvantaged by the lack of targeted governmental services available and the potential lack of social networks established to help provide them assistance in navigating healthcare systems as they age [ 7 , 8 ]. Older LGBT people may also have significant concerns about the need for institutional support in residential facilities for the aged due to inherent social prejudices [ 7 ].
Allocation of Resources, Empowerment, and Equity
Any discussion of sex and gender requires acknowledgement of the unequal distribution of assets and power as well the existence of harmful gender norms. The differential distribution of, access to, and control over resources has an effect on health. Health is positively associated with gender equity and lack of equity has a distinctly negative impact on health [ 1 , 17 ].
A key predisposing factor for an individual’s health is their level of education, which is also a driver of health literacy. Women in a number of low-and some middle-income countries, particularly in Africa and Asia, are disadvantaged due to having lower literacy rates and significantly lower rates of access to primary and/or secondary schooling in contrast to their male counterparts [ 11 ]. Moreover, it has been established that a person’s level of education is positively correlated with their use of healthcare services such as preventive services, intake of fewer prescription medicines, and a lower likelihood of inpatient hospital stays [ 1 ]. The social practice of restricting women’s attendance in school has a distinct and long-lasting influence not only on the women’s health but also on the health of their children [ 11 ]. There is a growing body of evidence that points to the importance of women’s education for child survival rates.
Although the exact numbers are not known, we know women are particularly vulnerable to poverty and in general earn less than men. Women are also subject to higher rates of unemployment, with the unemployment gap in relation to men ranging from 15% higher in countries with developed economies to 40% higher in countries with developing economies [ 11 ]. Women are also more likely than men to be in nonformal employment for which they do not receive a salary [ 11 ]. Also, in most societies men continue to hold more political power and with it have greater rein over social and economic controls. The data is very clear with regard to the socioeconomic gradient; higher levels of wealth translate into better health, and women’s financial status within most societies is less than males.
However, we have yet to gain adequate insights into how gender equity is affected within a socioeconomic level. We do not know if there is any difference between women and men in terms of their access to health or in their health outcomes within the same impoverished household.
With respect to LGBT populations, for the most part they are excluded from mainstream health policy which by nature remains largely hetero-centric. These populations are rarely considered within healthcare systems outside of the domain of HIV/ AIDS and other related diseases. Moreover, the LGBT population is largely missing from inclusion in the health disparity and diversity discussions occurring within countries such as the USA and Canada [ 7 , 8 ]. The focus is limited to more ‘visible’ groups such as racial and ethnic minorities. Since LGBT populations are not readily identifiable, they are usually absent from national data sets such as health surveys, censuses, and epidemiological studies. There are either limited or inadequate measures used to identify these populations. If present they are often limited to a single question related to ‘sexual preference’ which provides minimal and possibly slanted information. Finally, the structural barriers faced by LGBT populations are significant and include the limited knowledge of health care professionals, healthcare professionals’ bias which may be largely unintended, and the lack of legal status which can prevent a partner from being able to participate in health consultations or decision making in most countries [ 7 ].
The Final Word
The effects of gender inequities on global health are clear and far reaching. Their magnitude is a potent driver and catalyst for change. In an attempt to address these disparities, gender mainstreaming has evolved as a process in which issues related to gender inequities are given attention when making policies, designing programs, and providing services. This is included within both the legislative and the financial domains. While gender mainstreaming goes beyond the health sector, it is a critical element within it. In theory it should be framed by human rights, be inclusive of men, women, and LGBT people, and span preventive, curative, and rehabilitative healthcare services. While gender mainstreaming as a concept has great merit, it remains more of a promise than a widespread practice.
Another strategy aimed at addressing sex-based differences is the intentional increase in women within the healthcare professionals, within leadership positions in healthcare institutions, and within key political roles. While this intervention is admirable, it will by itself do little to affect equity within health systems since it is not a panacea for creating gender-sensitive health systems. The issue is far more complex and the interventions need to address inequity in broader terms.
Further, while the call for universal healthcare is well intentioned, it may have little or no impact on the gender-related disparities inherent in health systems unless we also address empowerment, access to education, gender-based violence, and hetero-centricity; these societal factors are prerequisites for the desired sea change and without them there will be little movement in terms of improving the overall health of society at large.
At the core of health systems is the tenet ‘to put people first’. To do this we must put sex and gender front and center. Although gender medicine is not a new therapeutic area, it is a new dimension for healthcare professionals and healthcare systems. Since healthcare systems are shaped by the society in which they operate, the change which needs to occur must permeate how these systems operate and how people relate as well as how people operate within these systems.
Ultimately, the success of a sex-and gender-based approach to health will be dependent on healthcare professionals who, among other actions, will need to play a leadership role as advocates in order to break the cycle of gender-based neglect. Advocacy and action must occur in a number of domains including policy, research, healthcare professional education, and clinical practice guidelines. Available and additional evidence needs to be generated and then put into practice across all of these domains. Additionally, education of patients must be coupled with broad awareness of all healthcare consumers.
Men, women, and LGBT people are waiting for healthcare systems that minimize inequities in health status, disease distribution, and access to services. They are also waiting for gender-sensitive approaches to their care. Let us not keep these patients waiting.
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6 Juel K, Christensen K: Are men seeking help too late? Contacts to general practitioners and hospital admissions in Denmark 2005. J Public Health (Oxf) 2007;30:111–113.
7 Gay and Lesbian Medical Association and LGBT Health Experts Healthy People 2010: Companion Document for Lesbian, Gay, Bisexual and Transgender (LGBT) Health. San Francisco, Gay and Lesbian Medical Association, 2001.
8 Mule NJ, Ross RE, Deeprose B, et al: Promoting LGBT health and wellbeing through inclusive policy development. Int J Equity Health. 2009;8: 18.
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Paula R. DeCola, RN, MSc Pfizer Inc. 235 East 42nd Street, MS 219-9-11 New York, NY 10017 (USA) Tel. +1 212 573 7473, E-Mail paula.decola@pfizer.com
Social and Biological Determinants in Health and Disease
Schenck-Gustafsson K, DeCola PR, Pfaff DW, Pisetsky DS (eds): Handbook of Clinical Gender Medicine. Basel, Karger, 2012, pp 18–36
A Global War against Baby Girls: Sex-Selective Abortion Becomes a Worldwide Practice
Nicholas N. Eberstadt
American Enterprise Institute, Washington, D.C., USA
Over the past three decades the world has come to witness an ominous and entirely new form of gender discrimination: sex-selective feticide, implemented through the practice of surgical abortion with the assistance of information gained through prenatal gender determination technology. All around the world, the victims of this new practice are overwhelmingly female - in fact, almost universally female. The practice has become so ruthlessly routine in many contemporary societies that it has impacted their very population structures, warping the balance between male and female births and consequently skewing the sex ratios for the rising generation toward a biologically unnatural excess of males. This still-growing international predilection for sex-selective abortion is by now evident in the demographic contours of dozens of countries around the globe - and it is sufficiently severe that it has come to alter the overall sex ratio at birth of the entire planet, resulting in millions upon millions of new’missing baby girls’each year. In terms of its sheer toll in human numbers, sex-selective abortion has assumed a scale tantamount to a global war against baby girls.
Copyright © 2012 S. Karger AG, Basel
Initial Signal in China
A regular and quite predictable relationship between total numbers of male and female births is a fixed, biological characteristic of human populations. The discovery of the consistency, across time and space, of the sex ratio at birth (SRB) for human beings is one of the very earliest findings of the modern discipline of demography. Medical and demographic research subsequently identified some differences in SRB that correspond with ethnicity, birth order, parental age, and other factors [ 1 – 3 ], but such differences were always quite small; until the 1980s, the SRB for large human populations tended to fall within a narrow range, usually around 103-106 newborn boys for every 100 newborn girls and centering not above 105. Until the 1980s, exceptions to this generality were mainly registered in small populations and attributable to chance.
Table 1. The ever-increasing gender imbalance in China. Reported SRBs and sex ratios of the population age 0-4 years: 1953-2005 (boys per 100 girls)
Year of census or survey
Sex ratio of births
Sex ratio of the population age 0-4


Sources [ 46 ; Chinese Academy of Social Science, unpubl. data]. Reprinted with permission.
The modern phenomenon of biologically unnatural increases in the SRB was first noticed in the 1980s - in China, the world’s most populous country. In 1979, China promulgated its forcible antinatalist ‘One Child Policy’ [ 4 ]. This program continues to be enforced to this day, albeit with regional and temporal variations in severity [ 5 ]. In 1982, China’s national population census - the first to be conducted in nearly two decades - reported an SRB of 108.5, a striking and disturbing demographic anomaly. Initially, researchers surmised that this abnormal imbalance might be in large part statistical artifact, under the hypothesis that Chinese parents might be disposed to conceal the birth of a daughter so as to have another chance for a son, given the birth quotas associated with the ‘One Child Policy’. 1 However, successive Chinese population censuses registered ever-higher SRBs. By the 2005 ‘mini-census’ (1% intercensal survey), China’s SRB approached 120 - and the reported nationwide sex ratio for children under 5 was even higher ( table 1 ). 2 Over the last two decades some discrepancies and inconsistencies among Chinese data sources - census numbers, vital registration reports, hospital delivery records, and school enrollment figures - have been identified with regard to SRBs and child sex ratios [ 8 ]. However, there is absolutely no doubt that distorted sex ratios for newborns and children prevail in China today - and that these gender imbalances have increased dramatically during the decades of the ‘One Child Policy’.
Chinese census data outline the basic geo-demography of China’s imbalanced SRBs. For the country as a whole, SRBs since 1982 have consistently been lowest for China’s cities and highest for rural areas. In China’s 2005 ‘mini-census’, reported SRBs were roughly 123 for rural areas, 120 for towns, and 115 for cities [ 6 ]. However, there are major SRB variations within China at the regional level; as of 2005, only three provinces reported essentially ‘normal’ SRBs, while many more reported SRBs of 125 or more. Two provinces reported levels in excess of 130 ( fig. 1 ). The geography of China’s gender imbalance is further highlighted by a county-level breakout of sex ratios for young children in the year 2000 ( fig. 2 ). As may be seen, sex ratios are essentially ‘normal’ (105 or lower) in much of Western China and along parts of the country’s northern border - areas where non-Han ethnic minorities predominate. Higher-than-normal gender imbalances are seen in China’s east and south populated primarily of the Han majority. There are tremendous variations in the extremity of the condition within this Han expanse: a number of inland and coastal areas stand out as epicenters of the problem and are marked by concentrations of counties, each encompassing millions or tens of millions of people, wherein child sex ratios of 150 or greater prevail. Demographers Guilmoto and Oliveau [ 10 ] describe these radical-imbalance areas as ‘hot spots’. This phenomenon has diffused across China’s population over the past three decades and figure 2 may be regarded as the map of a rising national epidemic.
Parity-Specific Imbalance
Further light is cast on the epidemiology of Chinese SRB imbalances by patterns of parity-specific SRBs - that is to say, SRBs by birth order - since 1982 ( fig. 3 ). Significantly, SRBs for firstborn Chinese children have remained relatively low and were actually in the biologically ‘normal’ 105 range until the early 1990s. For higher-parity births, on the other hand, SRBs from the late 1980s onward have been stratospheric - biologically impossible - and continued to rise until the year 2000, at which time the SRB for higher-parity births exceeded 150 (higher-parity SRBs reportedly declined somewhat between 2000 and 2005 - but as of 2005 they nonetheless amounted to 143 for second births and to 156 for third births). At one point, researchers hypothesized that the emerging gender imbalance in China was primarily a consequence of the spread of the hepatitis B virus, which is known to skew SRBs in favor of male babies in maternal carriers [ 11 ] - but clearly that theory cannot account for the extraordinary and continuing disparities between first births and higher-order births in China. Instead, it is by now widely recognized that these gender disparities are the consequence of parental intervention through the agency of medically induced abortion and prenatal gender determination technology. Chinese parents appear to have been generally willing to rely upon biological chance for the sex outcome of their first baby - but with increasing frequency they relied upon health care technology and services to ensure that any second-or higher-order baby would be a boy. 3

Fig. 1. China’s reported SRB by province, 2005 (boys per 100 girls). Source [ 20 ].

Fig. 2. Reported child (age 0-4 years) sex ratio in China by county, 2000. Source: Guilmoto and Oliveau [ 10 ]. Reprinted with permission.

Fig. 3. China: Reported SRBs by birth order (parity), 1982-2005. Sources [ 9 , 16 – 20 ]. Reprinted with permission.
The critical health service elements in this tableau are China’s universal and unconditional availability of abortion conjoined with access to reliable and inexpensive obstetric ultrasonography. According to Chinese researchers, in 1982 diagnostic ultrasound scanning devices were available in health clinics in about one sixth of Chinese counties; over half of Chinese counties had them by 1985, and virtually all had them by 1990 [ 14 ]. By the year 2000, sex-selective abortion had become commonplace in China: rough calculations for that year suggest that no less than half of the nation’s higher-parity female fetuses were being aborted and that well over half of all abortions were female fetuses terminated as a consequence of prenatal gender determination. In effect, most of contemporary China’s abortions are thus intentional female feticides.
Drivers of Imbalance
Though Western sensibilities may be inclined to attribute the SRB imbalances to ‘backward’ thinking in China, important basic facts are uncomfortably inconsistent with that proposition. For one thing, the abnormal sex ratios appear to be almost entirely a Han phenomenon within China, and China’s Han tend to be better educated and more affluent than the country’s non-Han minorities. However, it should also be noted that SRBs are lower in urban than in rural China. However, these differences may be more related to lower fertility levels in urban areas than to levels of education and income since lower fertility levels tend to be associated with lower SRB imbalances in comparison to those seen with higher-parity births. Further, the rise in SRB imbalances has been occurring during a time when China has enjoyed a historically extraordinary surge of development and prosperity. Between the 1982 and 2005 censuses, China’s reported adult (15+) female illiteracy rate dropped from 25 to 4%, and over roughly that same period the mean years of schooling for Chinese women rose by nearly 50%, from 5.4 to 8.0 [ 15 – 20 ]. Moreover, China’s estimated per capita income jumped nearly five-fold between 1982 and 2005 [ 21 ], while the fraction of the population living in extreme poverty (as defined by the World Bank) plummeted from roughly 75% in 1981 to roughly 15% in 2004 [ 22 ]. These advances have also been occurring during a time when, despite continuing political restrictions and censorship, China has been becoming vastly more open to the outside world than it was in the early 1980s. China’s increasingly unnatural sex ratios for babies and children and its growing army of ‘missing girls’ must therefore be regarded as a feature - indeed, a defining feature - of ‘globalization with Chinese characteristics’. It is worth noting that Beijing outlawed prenatal sex determination in 1989 [ 23 ] and criminalized sex-selective abortion in 2004 [ 24 ] - yet these legal strictures have obviously been ineffective in reversing this cultural phenomena. China’s unnatural long-term rise in SRBs emerged under a state-run population control program, but draconian family planning programs are neither a necessary nor a sufficient condition for widespread female feticide. This much is evident from SRB trends in East Asia’s four ‘Little Tigers’: Hong Kong, Singapore (more specifically, Singapore’s ethnic Chinese), South Korea, and Taiwan. All of those societies maintain voluntary family planning programs - nevertheless, each of them has registered disturbing increases in SRBs in the era of unconditional abortion and widespread access to inexpensive obstetric ultrasonography ( fig. 4 ). In all four of these affluent and highly educated populations, SRBs approaching the dawn of the 21st century were a biologically impossible 108 or higher - and, just as in China, SRBs were typically lowest (often ‘normal’) for the firstborn babies and suspiciously elevated for all higher-parity births [ 25 ], a tell-tale sign of parental intervention through sex-selective abortion. Like China, these ‘Little Tigers’ all had laws on their books proscribing prenatal gender determination and/or sex-selective abortion that did not forestall subsequent increases in their SRBs. Of all the ‘Little Tigers’, South Korea reached the most demographically disfiguring heights: an SRB of well over 114 in the early 1990s, comparable to China’s at that time. But South Korea’s SRB declined steadily thereafter, and by 2009 it was according to official state statistics a practically ‘normal’ 106 [ 26 ] - a matter to which we shall return.

Fig. 4. SRBs reported in East Asia, 1980-2005 (3-year averages). Source: Shuzhuo [ 9 ]. Reprinted with permission.
One commonality to China, and the four ‘Little Tigers’, would be a Confucian cultural heritage, which places an imperative on continuing a family’s lineage through the male heir as a metaphysical key to greater universal virtue and harmony. It is noteworthy that Japan - an East Asian society without a strong Confucian tradition but with easy access to abortion and obstetric ultrasonography and with very low fertility rates, just as in China and the four ‘Little Tigers’ - has always reported an SRB well within biological human norms.
As it happens, however, a strong Confucian heritage is not a unique identifier of societies at risk of mass female feticide. In Southeast Asia, Vietnam - a society with a strong Buddhist tradition - now evidences strong indications of rising SRBs [ 27 ]. Like China and the ‘Little Tigers’, Vietnam is a subreplacement fertility society with easy access to abortion and an increasing diffusion of ultrasound technology. 4 Between 1999 (according to data from annual sample population surveys) and 2009 (the year of the country’s latest population census), Vietnam’s SRB appears to have risen from about 105 to over 110. As in China and the ‘Little Tigers’, SRBs are markedly elevated for higher order births (especially for third or higher births). Vietnam’s upsurge in SRBs, it may be observed, coincided with a period of rapid material advance (between 1998 and 2008, the per capita output is estimated to have jumped by 80% [ 27 , 28 ]), and positively correlates with prosperity within Vietnam today, with the country’s lowest SRBs registered by the poorest income quintile and the highest registered by the most affluent. Like China and the ‘Little Tigers’, Vietnam also has laws on the books that make sex-selective abortion nominally illegal.
By this point in our discussion, a consistent etiology of unnaturally high SRBs (the female feticide that underpins them) can be described. These phenomena appear to arise from a collision of three forces: (1) local mores that uphold a truly merciless preference for sons; (2) low or subreplacement fertility trends, which freight the gender outcome of each birth with extra significance for parents with gender bias, and (3) the availability of health services and technologies (easy and affordable abortion and prenatal sex diagnostics) that permit parents to engineer the sex composition of their families - and, by extension, of their societies.
India’s Imbalance
India has a history of discrimination against girls and women through its customs of female infanticide, dowry killings, and ritual sati immolation of widows [ 29 ]. It has recorded pronounced and continuing fertility declines, and its past two decades of very rapid economic growth have been attended by increasing domestic diffusion of new technologies of every sort. With this as a backdrop, India would seem poised as a likely battlefield in the new global war against baby girls. Sure enough, both SRBs and child sex ratios have risen markedly for the world’s second most populous country since the early 1990s. According to India’s National Family Health Surveys (NFHS I-III), India’s nationwide SRB rose from around 105 in 1979/1992 to 109 for 2000/2006; more recently the country’s National Sample Survey placed the SRB for 2004/2006 at 112 [ 30 ]. According to India’s population censuses, the nationwide sex ratio for children under 7 years of age rose from 105 in 1991 to 109 in 2011 [ 31 ]. Geographically, India’s gender imbalances are most extreme in India’s northwest. In the states of Haryana and Punjab, the 0-6 sex ratio is now close 120, or even above 120, while in Delhi, India’s capital, the sex ratio for children under 7 is currently a reported 115 ( fig. 5 , 6 ). Socioeconomically, SRBs and child sex ratios in India today correlate positively - not negatively - with education, income, and urbanization. Like the aforementioned countries with high SRBs, sex selective abortion is illegal in India.

Fig. 5. India: reported sex ratios for children ages 0-6 years by state, 2001 versus 2011. Source: Census of India [ 31 ].
Caucasus Region Imbalance
In the Soviet era, ultrasound diagnostics had been generally unavailable in West Asia within the Caucasus region. However, inferential evidence, including the increasing access to ultrasound diagnostic and newly increasing SRBs for higher-parity births, strongly suggests that these countries are subject to the same syndrome observed in so much of East Asia and South Asia. Since the end of the Cold War this area has arisen as another front in the global war against baby girls [ 32 , 33 ]. Between the final collapse of the Soviet Union in 1991 and the year 2000, SRBs in Armenia, Azerbaijan, and Georgia all rose from about 105 to about 120. More recent vital registration system data indicate that SRBs in the Caucasus have declined, but only slightly: to 116 in Armenia and Azerbaijan (as of 2008) and to 112 in Georgia (as of 2004).

Fig. 6. Reported child (age 0-6 years) sex ratio in India (reaggregated subdistricts), 2001. Source: Guilmoto and Oliveau [ 10 ]. Reprinted with permission.
Other Countries and Subpopulations
The ten societies with biologically unnatural SRBs examined thus far represent most of the world’s major religious and cultural traditions: Confucianism, Buddhism, Hinduism, Islam, and Christianity. However, these are by no means the only contemporary settings in which evidence of the phenomenon is emerging at a population-wide level ( tables 2 , 3 ). Recent vital statistics for places with complete or near-complete registration or census returns point to almost twenty additional countries or territories with populations of 1 million or greater having an SRB above 107. Other places in Asia with suspiciously high recent SRBs and/or child sex ratios include the Philippines, Brunei Darussalam, Papua New Guinea, Bangladesh, Kyrgyzstan, and Turkey. In the Middle East/North Africa, both Lebanon and Libya betray the same demographic characteristics. In Latin America and the Caribbean, elevated SRBs or child sex ratios are seen in Cuba, Puerto Rico, and El Salvador, but it is important to recognize that the phenomenon is now evident in over half a dozen European countries as well. Albania’s officially reported 2004 SRB was 113. In Serbia and Montenegro - portions of the former Yugoslavia - 2008 SRBs were 109 and 108, respectively, and in the nominally Catholic-majority populations of Austria (2008), Italy (2005), Portugal (2008), and Spain (2008), officially reported SRBs were all an anomalous 107.
Table 2. Countries with population over 1 million reporting SRBs over 107 in a recent year (and near-complete vital registration)
Country (year)
Sex ratio
Midyear population (2010), UNPD
Albania (2004)
El Salvador (2007)
Philippines (2007)
Libya (2002)
Serbia (2008)
Austria (2008)
Cuba (2008)
Italy (2005)
Kyrgyzstan (2008)
Portugal (2008)
Spain (2008)
All data are derived from civil registration, estimated at over 90% complete. Source [adapted from table 10 in 47 ].
Table 3. Countries with populations over 1 million reporting child (age 0-4 years) sex ratios above 107 in a recent population census

Biologically impossible SRBs are also now seen in the USA and the UK - within particular ethnic groups. In America, SRBs of 108 were characteristic of the ‘Asian-Pacific’ populations such as Chinese-Americans, Korean-Americans, and Filipino-Americans in the 2000 census [ 34 ] and in vital statistics thereafter - populations whose SRBs were within the ‘natural’ biological range a generation ago. In England and Wales, SRBs for Indian-born mothers have also risen markedly, from 104 in the 1980s to 108 in the late 1990s [ 35 ]. In both the USA and the UK, these gender disparities were due largely to sharp increases in higher-parity SRBs, strongly suggesting that sex-selective abortions were the driver. The US and UK cases also point to the possibility that sex-selective abortion may be common to other subpopulations in developed or less developed societies, even if these do not affect overall SRBs for the country as a whole.
The Demographic Effect
Sex-selective abortion is by now so widespread and so frequent that it has come to distort the population composition of the entire human species: this new and medicalized war against baby girls is indeed truly global in scale and scope. Estimates by the United Nations Population Division (UNPD) and the US Census Bureau’s International Programs Center (IPC) - the two major organizations charged with tracking and projecting global population trends - make the point ( tables 4 , 5 ). By the analysis of the IPC, as of 2010 a total of 21 countries or territories (including a number of European, Middle Eastern, and Pacific Island areas not yet mentioned in this chapter) had child (0-4 years of age) sex ratios of 107 or higher in the year 2010. The total population of the regions said to be beset by unnaturally high SRBs amounted to 2.72 billion, or about 40% of the world’s total population. For its part, the UNPD estimates that 24 countries and territories (a slightly different roster from that of the IPC, including some additional European, South American, Middle Eastern, Asian and Pacific settings not thus far mentioned) had SRBs of 107 or higher for the 2005-2010 period. The total population for these regions in 2010 was estimated at 2.74 billion, or about 39% of the world’s 6.8 billion population that same year. The estimated 2010 population for all of the places flagged by either the UNPD or the IPC for unnaturally high SRBs or child sex ratios would amount to 2.82 billion - about 41% of the total global population - and if we tally in the other places from tables 2 and 3 whose official demographic statistics report unnaturally high SRBs of child sex ratios, we would have a total of over 50 countries and territories accounting for over 3.2 billion people, or roughly 46% of the world’s total population.
By the reckoning of the UNPD, the overall global SRB has already reached biologically impossible heights in the era of sex-selective abortion, rising from 105 in 1975-1980 to 107 for 2005-2010. By the same token, the IPC puts the worldwide under-5 child sex ratio at 107.0 for 2010 (though its global estimates only extend back to the year 2000).
Table 4. UNPD estimates of countries with SRBs above 107 in 2010 and an implied ‘excess male’ population under 20 years of age

To go by both UNPD and IPC reconstructions of local age-sex structures, today’s unnaturally high SRB and/or child sex ratio societies would have had an aggregate ‘boy surplus’ of over 55 million boys and young men under the age of 20 by the year 2010. If we assume that the SRBs and child/youth sex ratios in these societies should be around 105, the unnatural ‘girl deficit’ for females 0-19 years of age as of 2010 would have totaled roughly 34-35 million by both UNDP and IPC figures ( tables 4 , 5 ). In both the UNPD and the IPC reckonings, the world’s two most populous countries, China and India, would account for the overwhelming majority (33-34 million) of the world’s ‘missing girls’ under 20 years of age in our era of sex-selective abortion. However, the implied UNPD and IPC totals for China and India themselves differ substantially, in accordance with their assumptions concerning such things as the extent of undercounting of girls. Irrespective of differences in IPC-and UNPD-based estimates for given countries, these global estimates for ‘missing girls’ under 20 are arguably quite conservative figures, excluding as they do numerous countries - some of them quite populous - where evidence of unnaturally high SRBs has been emerging from vital registration or national census data [ 36 ], and setting a ‘high bar’ as a threshold for calculations of ‘excess males’ (some researchers would, and in fact do, argue that benchmarks of 104, 103, or perhaps even lower would be suitable for such exercises).
Table 5. US Census Bureau estimates of countries with child (age 0-4 years) sex ratios above 107 in 2010and an implied’excess male’population under 20 years of age

Social Implications
The consequences of medically-abetted mass feticide are far reaching and manifestly adverse. In populations with unnaturally skewed SRBs, the very fact that many thousands - or in some cases, millions - of prospective girls and young women have been deliberately eliminated simply because they would have been female establishes a new social reality that inescapably colors the whole realm of human relationships, redefining the role of women as the disfavored sex in nakedly utilitarian terms and indeed signaling that their very existence is now conditional and contingent.
Moreover, enduring and extreme SRB imbalances set the demographic stage for an incipient ‘marriage squeeze’ in affected populations, especially where subreplacement is reducing the future pool of potential brides. China’s persistently elevated SRBs, for example, stand to transform it from a country where as of 2000 nearly all males (about 96%) had been married by their early 40s to one in which nearly a quarter (23%) are projected to be never married as of 2040, less than 30 years from now. 5 Such a transformation augurs ill in a number of respects. For one thing, unmarried men appear to suffer greater health risks than their married counterparts, even after controlling for exogenous social and environmental factors; 6 a sharp increase in the proportion of essentially unmarriageable males in a society with a universal marriage norm may only accentuate those health risks. In a low-income society lacking sturdy and reliable national pension guarantees for the elderly, a steep rise in the proportion of unmarried and involuntarily childless men begs the question of old-age support for that rising cohort. Some economists have hypothesized that mass feticide, in making women scarce, will only increase their ‘value’ [ 40 ] - but in settings where the legal and personal rights of the individual are not secure and inviolable, the ‘rising value of women’ can have perverse and unexpected consequences, including increased demand for prostitution and an upsurge in the kidnapping and trafficking of women. This phenomenon is now reportedly being witnessed in some women-scarce areas in Asia [ 41 ].
Finally, there is the speculative question of the social impact of a sudden addition of a large cohort of young ‘excess males’ to populations sustaining extreme SRBs: depending on a given country’s cultural and institutional capabilities for coping with this challenge, such trends could quite conceivably lead to increased crime, violence, and social tensions - or possibly even a greater proclivity for social instability. 7
All in all, mass sex selection can be regarded as a ‘tragedy of the commons’ dynamic, in which the aggregation of individual (parental) choices has the inadvertent result of degrading the quality of life for all - and some much more than others.
What are the prospects for mass sex-selective feticide in the years immediately ahead? Unfortunately, there is ample room for cautious pessimism. Although biologically unnatural SRBs now characterize an expanse accounting for something approaching half of humanity, it is by no means clear that this march has yet ceased.
As we have seen, sudden steep increases in SRBs are by no means inconsistent with continuing improvements in levels of per capita income and female education - or for that matter, with legal strictures against sex-selective abortion. Two of the key factors associated with unnatural upsurges in nationwide SRBs - low or subreplacement fertility levels and easy access to inexpensive prenatal gender determination technology - will likely be present in an increasing number of low-income societies in the years and decades immediately ahead. The third factor critical to mass female feticide - son preference - is perhaps surprisingly difficult to identify in advance. In theory, the overbearing son preference should be available from demographic and health surveys (DHS) - such as India’s National Family and Health Survey, which demonstrated that prospective mothers in the state of Punjab desired their next child to be male rather than female by a ratio of 10 to 1. 8 However, ironically, despite the many tens of millions of dollars that international aid and development agencies have spent on the hundreds of DHS surveys they have supported in low-income countries over recent decades, information on sex preference to date is almost never collected. Differential infant and child mortality rates arguably offer clues about son preference. Societies where female mortality rates exceed male rates may be correspondingly disposed to prenatal gender discrimination as well. According to WHO 2008 Life Tables, over 60 countries currently experience higher infant or 1-4 mortality rates for girls than for boys. The roster includes much of South-Central Asia (Afghanistan, Bangladesh, Nepal, Pakistan, Turkmenistan, and Uzbekistan), North Africa and the Middle East (Bahrain, Egypt, Morocco, Jordan, Oman, and Yemen), parts of Latin America and the Caribbean (Bolivia, Ecuador, Haiti, Honduras, Nicaragua, and Trinidad and Tobago), and over a dozen countries in sub-Saharan Africa, including the sub-Saharan demographic giants of Nigeria, Ethiopia, and Sudan [ 44 ]. If such gender bias in mortality turns out to be a predictor of sex selection bias, this global problem may get considerably worse before it gets better.
Considerations Moving Forward
There is, however, one country thus far that has managed to return from imbalanced SRBs to normal ratios: South Korea. There is still considerable dispute about the factors involved in this turnaround [ 45 ], with many institutions and actors ready to take credit (as the old saying goes: success begets many fathers). Available evidence, however, seems to suggest that South Korea’s U-turn in SRBs was influenced less by government policy than by civil society: more specifically, by the spontaneous and largely uncoordinated congealing of a mass movement for honoring, protecting, and prizing daughters. In effect, this movement - drawing largely but by no means exclusively on the faith-based community - sparked a national conversation of conscience about the practice of female feticide - a conversation that was instrumental in stigmatizing the practice. This was not altogether unlike the way in which nationwide conversations of conscience had helped to stigmatize international slave-trading in other countries in earlier times. The best hope today in the global war against baby girls may be to carry this conversation of conscience to other lands. Medical and health care professionals - without whose assistance mass female feticide could not occur - have a special obligation to be front and center in this dialogue.
The author would like to thank Mr. Dale Swartz and Ms. Kelly Matush for overall research assistance for this chapter, and Ms. Heesu Kim and Mr. Mark Seraydarian for identifying those DHS surveys in which parental gender preferences for the next birth are specified. Ms. Laura Kelly of Battelle provided extremely constructive criticism of an earlier draft. All remaining errors are the author’s responsibility.
1 Johannson and Nygren [ 6 ], for example, concluded that much of the contemporary ‘missing girl’ puzzle in China could be explained by hidden daughters, while also pointing to the likelihood of some sex-selective infanticide.
2 Chinese authorities conducted a national population census for November 2010, but the detailed results from that count are not yet available, and the initial communiqué on that census does not mention the country’s SRB [ 7 ].
3 Although China’s population program is known as the ‘One Child Policy’, it does in practice permit the birth of some second, third, and even higher-order babies: for the country as a whole, the total fertility rate (or number of births per woman per lifetime) is estimated by the UNPD as 1.64 for the 2005-2010 period, and by the US Census Bureau International Data Base at 1.54 for the year 2010 [ 12 , 13 ].
4 According to Vietnam’s Ministry of Health, annual ultrasound tests nationwide rose more than tenfold between 1997 and 2007, i.e. from 1 million to 10.8 million; these data refer to medical imaging for all purposes, not only obstetrics [ 28 ].
5 Calculated using ProFamy software [ 37 ] as described in Yi, et al. [ 38 ].
6 For an overview and evaluation of the growing literature on the relationship between marriage and health, see Wood et al. [ 39 ].
7 For a decidedly ‘pessimistic’ but studied assessment of these prospects, see Hudson and den Boer [ 42 ].
8 For example: Macro International, a USAID contractor, archives over 200 DHS surveys for 75 countries - but only 7 of these for 4 countries (India 1992/1993, 1998/1999, 2005/2006; Jordan 2002; Pakistan 1990/1991, and Yemen 1991/1992, 1997) contain specific questions on parental sex preference for the next birth. The DHS surveys in question are available electronically at Measure DHS [ 43 ].
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Nicholas N. Eberstadt, PhD American Enterprise Institute 1150 17th Street NW Washington, DC 20036 (USA) Tel. +1 202 862 5825, E-Mail eberstadt@aei.org
Social and Biological Determinants in Health and Disease
Schenck-Gustafsson K, DeCola PR, Pfaff DW, Pisetsky DS (eds): Handbook of Clinical Gender Medicine. Basel, Karger, 2012, pp 37–51
Fetal Programming
Marek Glezerman
Departments of Obstetrics and Gynecology, Helen Schneider Hospital for Women, Rabin Medical Center, Petah Tiqwa, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
In his book‘Life in the Womb’, Nathanielisz aptly states that’…how we are ushered into life, determines how we leave…’. This, in essence, is the basic idea of fetal programming, namely the understanding that during intrauterine life the stage is set for future health and disease. During fetal life, epigenetic changes aim to prepare the fetus for his future life, and if this preparation turns out to be inadequate the risk of various diseases increases. In this chapter, hormonal and genetic aspects of fetal sex determination will be presented, the effects of exogenous toxins on the fetal environment will be discussed, and the effects of the hormonal milieu on the development of the fetus will be reviewed, including the sexual dimorphous brain. Fetal programming of adult disease will be exemplified by maternal nutrition and stress, and the concept of the pregnant mother as an information window to the outside world will be discussed. Other topics like the impact of the intrauterine environment on future IQ and sexuality will be mentioned, and obstetric implications of fetal programming will be considered.
Copyright © 2012 S. Karger AG, Basel
What Is Fetal Programming?
Modern obstetrics has seen dramatic changes in the past decades. We have learned to observe the unborn in utero, to diagnose a variety of pathologies, and to treat some of them in utero. The fetus has become a patient and modern obstetrics has matured into feto-maternal medicine. The latest development is the advent of the new concept of ‘fetal programming’ which is based on the understanding that the intrauterine environment can impose postgenomic changes that can have far reaching consequences on health and wellbeing which can affect the individual in adulthood as well as subsequent generations. Understanding the concept of fetal programming requires the understanding of epigenetics, which in essence is the nonmutational manipulation of genes without affecting their basic structure. While epigenetic modifications, by definition, do not change the DNA sequence per se, they may cause permanent modifications of the genome by changing the methylation of DNA or through some other similar processes. Gluckman and Hansen [ 1 ] have discussed the concept of ‘developmental plasticity’ which is based on the notion that irreversible epigenetic changes due to a specific environment may lead to the development of different phenotypes from a single genotype. This is also one of the reasons why genotypically similar siblings or monozygotic twin pregnancies can be rather different phenotypically, depending on the expression of their respective genome. Thus, eventually, it is not the genome which exclusively governs our present and future but how the genome is expressed, and this can be influenced by the intra-and extrauterine environment and may therefore also be to a considerable extent under our control. Fetal programming may create predisposition factors for adult disease and is also crucial for behavioral and cognitive normalcy or deviation thereof. The importance of fetal programming cannot be overstated. Currently, much scientific effort is being invested to gather more hard evidence on this fascinating topic. Consider Project VIVA ( http://www.dacp.org/viva/index.html ), an NIH-and CDC-sponsored pioneering longitudinal cohort study which is following over 2,500 children starting in their intrauterine life. Since September 2008, over 50 studies have been published by the group, in addition to numerous book chapters and editorials. An even more monumental longitudinal study was initiated in 2003, namely ‘The National Children’s Study’ ( http://www.nationalchildrensstudy.gov/Pages/default.aspx ). This study aims to enroll 100,000 American women before and during pregnancy and to examine the effects of the environment and genetics on the growth, development, and health of offspring from before birth until the age of 21. Interagency and congressional funding of the study during the past decade has exceeded USD 600 million.
Hormonal and Genetic Aspects of Fetal Sex Determination
One of the most crucial time windows which the human embryo faces occurs during a few hours sometime between 41 and 44 days after conception (in obstetrical terms during the 6th week of pregnancy). During these few fateful hours in that narrow time window, nature determines whether the developing fetus will be phenotypically male or female. Of course, chromosomal sex determination has already taken place during fertilization but, phenotypically, all odds are still open. If nothing happens during this time window, the embryo will by default develop into a phenotypic female. However, if a Y chromosome is present and a very specific single gene which is located on the short arm of that Y chromosome is activated, then the primitive gonad develops into a testicle and soon begins to secrete large amounts of testosterone and the embryo begins its development to become a phenotypic male. This sex-determining gene is named after its location on the Y chromosome, hence sex-determining region on the Y chromosome, in short SRY. The ensuing enormous testosterone production of the fetal testes will have a crucial impact on the subsequent development of intrauterine and extrauterine gender differences.
The chromosomal makeup and the hormonal environment and the appropriate functional receptors for various hormones thus determine the phenotypic sex.
Exogenous Effects on the Intrauterine Environment
It is now common understanding that prenatal life is no safe haven for the fetus and that the environment in which the pregnant mother lives has a direct impact on the development of the fetus. In effect, there is no other time throughout the life span of an individual where it is so intimately exposed to the environment. Whatever affects the pregnant mother may well affect her growing embryo and fetus, in many cases in a greatly amplified manner. The impact of exogenous toxins on the developing fetus is dependent on qualitative and quantitative factors and also on when they occur during the development of the fetus. First trimester exposure will generally have teratogenic effects while second and third trimester exposure will more often be expressed in growth restriction and organ failure.
Environmental toxins are abundant. Whyatt et al. [ 2 ] examined the home use of pesticides (mostly against cockroaches) in a cohort of 314 pregnant women from an urban minority group. More than 85% reported the use of pesticides in their home and all had detectable blood levels of at least three pesticides, which are known neurotoxins for the developing fetus and may cause permanent brain damage that may even be transmitted to subsequent generations. Alcohol is a good example of how the intrauterine environment may be affected by exogenous toxins resulting in an enormous negative impact on the fetus and embryo. Up to 1% of US live births are affected by fetal alcohol spectrum disorders (FASD), which is defined by any impairment related to fetal exposure to alcohol, and 0.05-0.5% of live births are affected by the devastating results of fetal alcohol syndrome [ 3 ]. It is estimated that alcohol consumption during pregnancy is responsible for more cases of mental retardation in the USA than all other known causes combined, including chromosomal aberrations [ 3 ]. Unfortunately, there is virtually no threshold for alcohol toxicity, and postconceptional alcohol consumption by the pregnant woman, i.e. before she even knows about her pregnancy, may be as hazardous to the fetus or even more so than throughout pregnancy. Tobacco is another example: maternal smoking affects the developing fetus directly and causes reduced placental perfusion, lower birth weight, and a whole spectrum of adverse outcomes in the fetus and newborn and in later life. Xiao et al. [ 4 ] showed in a rat model that intrauterine exposure to nicotine increases the blood pressure response to angiotensin II in adult offspring. This phenomenon is gender specific as it could be demonstrated in male rats but not in female rats. Prenatal exposure to tobacco also increases the prevalence of cognitive and auditory processing deficits in the adult offspring, probably based on thinning of the cerebral cortex, and is more commonly observed in female adolescents than in males. Some other adverse effects also seem to be sex specific. Jacobsen et al. [ 5 ] evaluated 181 male and female smokers and nonsmokers with or without prenatal exposure to maternal smoking. Individuals exposed prenatally to nicotine showed a reduction of cortical cholinergic markers on which attentional function is highly dependent. Reductions in auditory and visual attention were greatest among females who were exposed prenatally to nicotine and who were smokers themselves. Intrauterine exposure to nicotine in males was associated with marked deficits in auditory attention.
Effects of Intrauterine Testosterone
The male gonad commences testosterone secretion as early as the 7th week of pregnancy. Testosterone levels peak around 14-18 weeks of gestation and testosterone levels in the developing male fetus may become close to adult levels. Testosterone exerts manifold effects on the developing organism, like sex-specific development of genitalia and growth rate. The effect of fetal sex steroids on mammalian brain development is most striking. Dependent on the availability of testosterone receptors, testosterone affects cell apoptosis and is involved in the establishment of neural connectivity. The results of this development are far reaching and are of crucial importance for ‘male’ behavior after birth and throughout life, including childhood play behavior, and may also be involved in the establishment of sexual orientation and sexual identity. High exogenous or endogenous testosterone levels in female embryos (or neonates) will lead to behavior patterns typical of males. On the other hand, neonatal castration in male rats or rhesus monkeys will lead to typical female behavior. In humans, much insight related to the effect of increased intrauterine levels of androgens has been gained from observations in females with congenital adrenal hyperplasia (CAH), a genetic disorder with autosomal recessive heritance. Affected individuals lack the enzyme 21 - hydroxylase (21 - OH) and produce therefore high levels of testosterone by the end of the first trimester of pregnancy. Phenotypically, these girls are born with various degrees of genital virilization or ambiguous genitalia. In spite of successful postnatal correction of the hormonal imbalance by corticosteroid treatment, affected females often present with various degrees of boy-typical behavior including toy preference. Later in life, women with CAH tend to be more often homosexual or bisexual than unaffected sisters or controls [ 6 ] and they may later in life show lower verbal capabilities, enhanced spatial abilities, and increased aggression during adolescence - all features which are usually associated with ‘maleness’. An opposite experiment of nature is the X-linked ‘androgen insensitivity syndrome (AIS)’ in genetic males, which is characterized by adequate intrauterine testosterone secretion but lack of functional receptors. Affected individuals are very rarely diagnosed postnatally as they are born as phenotypical females and also develop later in life as females, including behavior patterns, core gender identity, and sexual preference. Since affected individuals lack a uterus and ovaries, they usually present with primary amenorrhea which is not responsive to sex steroid treatment. Both CAH and AIS clearly demonstrate the crucial role played by intrauterine androgen levels and its functional receptors on subsequent physical, behavioral, and cognitive development. Excessive prenatal exposure to testosterone has been implicated in the development of dyslexia and autism [ 7 ]. On the other hand, reduced levels of fetal testosterone can be found in situations where the pregnant women is under acute and chronic stress, such as in times of war or when exposed to natural or personal disasters. Prenatal maternal stress and anxiety have been shown to be associated with impaired neurodevelopmental outcomes, including attention deficit and hyperactivity in boys [ 8 ].
The Sexual Dimorphous Brain – Organizational and Activational Effects of Sex Hormones
Hormones seem to exert a bitemporal effect on the brain. The organizational effect induces specific cell processes, occurs during intrauterine life, and permanently determines the development and function of sex organs, the brain, and other bodily systems. The activational effects may be transient or permanent, may occur throughout life, or may not occur at all. While this two-process theory has been challenged as being overall simplicist, it is helpful for the purpose of understanding the way sex hormones affect our brain. Juvenile play behavior has been used traditionally as an indicator of the degree of masculinization or feminization of offspring. Organizational and activational effects of testosterone also seem to be involved in inflammatory pain and response to morphine analgesia. This may explain the reported higher pain thresholds in men compared to women.
The sexual dimorphous development of the brain has fascinated researchers for over a century [ 9 ] and it is now generally accepted that fetal testosterone secretion plays a crucial role in the differentiation process. This has been demonstrated in animal studies as well as in humans [ 9 ]. Sex dimorphism of the human brain is evident at the cellular level, in the synaptic and dendritic organization, and also in the volume of specific cell groups and nuclei [ 7 ]. In the rat brain, the sexually dimorphic nucleus of the preoptic area (which also has a human equivalent) is such an example. In the human brain, dimorphic changes have been reported in the hypothalamus, cortex, and amygdale. Of great importance in this context is the hypothalamus which governs central functions like reproduction, eating, and sleeping. Gender differences in these major functions are partly a result of brain dimorphism. These differences are governed to a great extent by intrauterine levels of sex hormones, which exert organizational and activational effects. With the advent of functional MRI the brain, as the most complex organ in the human body, has become more accessible to functional neuroresearch. Moreover, while until rather recently it has been assumed that the brain, once established, is no longer capable of neurogenesis, there is now evidence that in primates new neurons are being created throughout life in various parts of the neocortex. This phenomenon of brain plasticity which includes anatomical and functional changes of the brain in response to environmental stimuli is of paramount importance and reflects the sensitivity of the brain to input. Again [ 3 ], an eminent genetician has stated that: ‘from the perspective of brain neuroscience, the environmental world of the developing embryo and fetus is as important as any information by the genes’. If both sides of the brain were to be constructed as mirror images, like mirrored hard disks, the resulting redundancy would provide a readily available repair resource to correct focal insults. Nature has implemented such a strategy for chromosome pairs but not for the brain. Here nature has opted mainly for maximal usage of available ‘real estate’ resources at the expense of redundancy. Therefore many (but not all) activity centers in the brain are unilateral. This modification of lateralization is neither predetermined solely by genetics nor absolute. Sex differences in lateralization have been the object of great scientific interest and the functional organization of laterality of language function has been of particular interest. Several language-related tasks are more left lateralized in males and more bilateralized in females. The corpus callosum is the main conduit of information between the two hemispheres of the brain and any asymmetric development may affect intrabrain connectivity between homologous and heterologous brain foci. Not only the corpus callosum but also the hemispheres show sexual differences which are related to fetal testosterone levels. Increased fetal testosterone levels in the male lead to a smaller corpus callosum and hence decreased connectivity between the left and the right brain. This may be the cause for greater lateralization of various cognitive functions and may explain why females use both sides of their brains more easily [ 7 ]. Using high resolution MRI in a cohort of 28 boys whose mothers had undergone second trimester amniocentesis, Chura et al. [ 9 ] studied the correlation of fetal testosterone levels with the size and the symmetry of the corpus callosum. The authors observed a positive correlation between fetal testosterone levels and increasing rightward asymmetry of a posterior subsection of the corpus callosum leading to an increased size of the right part of this particular segment.
Intrauterine Exposure to Sex Steroids and Physical, Cognitive, and Behavioral Outcomes
Baron-Cohen et al. [ 7 ] discussed a number of amniocentesis-based correlational studies, which indicate a positive correlation between the mental rotation rate and fetal testosterone and an inverse relation between fetal testosterone levels and language comprehension. The authors used stored samples of amniotic fluid and performed longitudinal studies in these ‘amniocentized children’ over 48 months after delivery. At 12 months of life they correlated fetal testosterone (fT) and the ability to make eye contact as a marker for social development in 71 children. Girls made significantly more eye contact than did boys. Eye contact decreased with increasing levels of fT. The authors further examined language development between 18 and 24 months of age in 87 toddlers and found that girls had a significantly higher vocabulary size than did boys and that there was a significantly inverse relationship between fT and vocabulary size for the children as a group but not within either sex group.
Maternal and Fetal Nutrition and Programming of Adult Disease
The concept of a relationship between fetal undernutrition and subsequent development of adult disease was introduced two decades ago by Barker et al. [ 10 ]. The ‘Barker theory’ or the ‘fetal origin hypothesis’ states that low birth weight reflects intrauterine malnutrition which programs the fetus for later cardiovascular disease, diabetes, and hypertension. Today it is generally accepted that the maternal diet affects fetal health and that maternal nutrition and specifically undernutrition with a low protein diet may be associated with subsequent development of obesity, cardiovascular disease, and hypertension. Leeson et al. [ 11 ] showed that low birth weight is associated with impaired endothelial function in childhood, which is an important risk factor for subsequent cardiovascular disease. The discovery that endothelial dysfunction in adults may be due to prenatal life events is of great importance since it indicates that atherosclerosis may also have its roots in prenatal events which are not genetically controlled. The authors calculated the relation between birth weight and endothelium-dependent flow-mediated dilatation (FMD) and concluded that a 1-kg difference in birth weight is equivalent to 4.5 cigarette pack-years as far as risk for subsequent vascular disease is concerned. This means that the adverse impact of reduced birth weight on vascular function across the birth weight range is as great as the effect of smoking. The correlation between reduced caloric intake during pregnancy and adverse fetal outcomes has been studied in populations in times of war and natural catastrophes. From November 1944 to May 1945, the German blockade of Western Netherlands led to what has been termed ‘The Dutch Famine or Hungerwinter’. Rations went as low as 400 calories a day, equivalent to 25% of the minimal daily requirement. At the Academic Medical Center in Amsterdam, the Dutch Famine Cohort Study was initiated; it investigates the outcomes of men and women who were born in the Wilhelmina Gasthuis in Amsterdam between November 1943 and February 1947 ( www.hongerwinter.nl ). Thanks to well-preserved documentation, the researchers were able to strongly corroborate the ‘Barker theory’. They found that individuals who were exposed in utero to malnutrition weighed 200-300 g less than controls and suffered later in life from a variety of diseases, including diabetes, cardiovascular disease, higher LDL/HDL ratios, obesity, coagulation disorders, hypertension, pulmonary disease, and renal disease. Ijzerman et al. [ 12 ] demonstrated in dizygotic, and hence genetically unlike twins that low birth weight was associated with insulin resistance and lower HDL levels, indicating a pathology independent of genetic factors. Intrauterine malnutrition seems to affect male and fetal fetuses differently. Sardina et al. [ 13 ] examined the central anorexigenic effects of insulin in rats. Female but not male adult rats who were exposed to intrauterine undernutrition developed in adulthood adiposity, impairment of hypothalamic insulin signaling, and loss of insulin-induced hypophagia.
It is becoming increasingly apparent that many forms of adult disease may have their roots in fetal programming and in early childhood. Obesity is one example: obesity has become a major public health problem affecting the majority of adults in the USA. Extremes of birth weight, i.e. low birth weight and increased birth weight, may cause future obesity and metabolic syndrome. It has been shown that prenatal androgen exposure of female mice causes impaired insulin secretion both as an organizational effect and as an activational effect which is based on defective islet cell function. Chronic diseases like osteoporosis, mood disorders, and psychiatric syndromes as well as polycystic ovary syndrome have been related to fetal programming. Other adult diseases such as cardiovascular disease, a variety of metabolic and endocrine pathologies, diabetes, and various other diseases may also be due to inadequate determination of set points during fetal programming. There is now preliminary evidence that eating disorders, which are more common in females that in males, are organized by low levels of prenatal testosterone and then activated by increasing estrogen levels during puberty in girls.
The Impact of Maternal Prenatal Stress on the Developing Embryo and Fetus
Four decades ago, Ward [ 14 ] reported that male rats which were exposed prenatally to stress showed low levels of male copulatory behavior but increased female lordotic sexual responses. There is a growing body of prospective data which links antenatal maternal stress with impaired, gender-specific emotional and cognitive development of offspring in childhood. Prenatal stress in pregnant animals can cause permanent impairment of neurodevelopment in offspring, including shorter attention spans, anxiety, and impaired cognitive function. Weinstock [ 15 ] showed in rats that maternal stress increases corticosteroid levels in the fetal brain and decreases testosterone levels and aromatase activity in male fetuses. Moreover, noradrenalin activity increased and dopamine activity decreased in male fetuses and levels became similar to those of female fetuses as a result of maternal stress. Male offspring had more learning deficits while female rats exhibited anxiety, depression, and an increased response of the pituitary-adrenal axis to stress. Based on rodent studies, Weinstock [ 15 ] further pointed out that maternal stress during critical periods of fetal brain development may exert long-term effects on the hypothalamus-pituitary-adrenal axis, including an impaired feedback mechanism and impairment of the circadian release of corticosteroids. This effect seems to be time sensitive and impinges on the fetal brain only during specific time windows. It has been shown that the increased incidence of schizophrenia in men whose mothers were subject to severe stress, as during the May invasion of the Netherlands in 1940, was restricted to the second trimester of pregnancy and did not occur during the first trimester of pregnancy [ 16 ]. Kashan et al. [ 17 ] studied a cohort of 1.3 million births in Denmark, which occurred between 1973 and 1995. They reported that death of a relative in the first but not in the second and third trimester of pregnancy was associated with an increased gender-specific risk for schizophrenia in offspring (adjusted RR 1.67; 95% CI 1.02-2.73). The incidence per 100,000 person-years was higher in males (55.4%) than in females (41.3%). The death of a relative occurring up to 6 months before conception had no such effect. Malaspina et al. [ 18 ] reported on a cohort of 88,829 births which occurred in Jerusalem between 1964 and 1976. They linked the data to Israels’ Psychiatric Registry and found an increased risk (RR = 2.3; 95% CI 1.1-4.7) for schizophrenia in individuals whose mothers were subject to substantial stress during the second month of pregnancy. In contrast to the report of Kashan et al. [ 17 ], they reported that the risk was higher in females (RR = 4.3; 95% CI 1.7-10.7) than in males (RR = 1.2; 95% CI 0.4-3.8). This sex preference for females is more in accord with other reports. It is noteworthy that attention deficit hyperactivity disorder (ADHD) symptoms have been observed in children and young adolescents whose mothers were suffering from increased anxiety during pregnancy and more often in males than in females. Although systems involving serotonergic and dopaminergic activity may also be involved, the most likely physiological and pathophysiological mechanisms by which maternal stress and PTSD affect offspring is the hypothalamic-pituitary-adrenal (HPA) axis. In essence, an increase in cortisol secretion in a person under stress is an adequate response as long as an intact feedback mechanism causes cortisol levels to decrease once the danger is over. However, if this feedback mechanism is impaired, adaptation to stress becomes inadequate. Steroid receptors are abundant in the hippocampus where mediation of feedback is concentrated. A reduction of steroid receptors in this area would affect an adequate feedback mechanism and could therefore interfere with adequate adaption to stress and the environment. Epigenetic processes may occur in the fetal hippocampus as a result of maternal stress which actually change the functional state of glucocorticoid receptors, cause a reduced feedback response, and consequently inadequately increase the cortisol response to stress later in life. This changed set point in the function of the HPA axis could then be one possible etiology for ADHD. Stress can, of course, not be totally avoided during pregnancy and a small to moderate stress level may actually be beneficial to the mental and physical development of offspring. This has been demonstrated by DiPietro et al. [ 19 ] who studied pregnant women who lived in a financially and emotionally stable environment but were exposed to moderately stressful situations. They reported that mild to moderate stress may enhance fetal maturation in healthy populations. Prenatal maternal stress may also lead to premature delivery and small-for-gestational-age babies. These in turn are risk factors for impaired cognitive development and may also affect neonatal neurobehavior.
The Pregnant Woman as an Information Source for the Growing Fetus
One important aspect of intrauterine programming may be the fetal response to signals conveyed by the pregnant women to her unborn child by which she ‘describes’ to her/him the outside world into which it is going to be born. Based on this information, the growing fetus prepares his/her physiological adaptation in order to cope with the outside world. This preparation for the postnatal world may cause what Gluckman and Hanson [ 1 ] have termed a ‘predictive adaptive response’ (PAR) and may have a profound impact on future health and disease. Obviously, genetic changes as a result of Darwinian selection could not occur rapidly enough to prepare the unborn for the specific environment into which it is going to be born, but epigenetic mechanisms can. Thus, adaptive changes in very early developmental stages in a single generation can equip the newborn with appropriate tools to meet ‘anticipated’ changes. If the newborn indeed faces the expected challenges, he will be well equipped. If, however, the environment has changed, his adaptive tools may be inadequate and he will actually be at a disadvantage. For example, maternal stress during pregnancy, which may lead subsequently to increased vigilance and higher awareness of potential threats in offspring, may be adequate if the new world is indeed full of danger. However, if the newborn is born into a quiet and protected world, his adaptive measures may be ill placed and his high vigilance and suspicion of his surroundings combined with rapid shifts of attention may express itself as attention disorders and even paranoia. Another example relates to the use of food: Desai et al. [ 20 ] restricted pregnant rams in food intake. This may have conveyed a signal to the fetuses about restricted postnatal food availability. When the newborns were given food ad libitum, they overate and developed obesity. When, however, intrauterine food restriction persisted after birth, the offspring developed like controls which were not food restricted before or after birth. Here is an interesting example of how external signals about the anticipated environment into which the fetus is going to be born are conveyed by the pregnant female to the developing fetus. Lee and Zucker [ 21 ] showed that the length of days during gestation of voles affects the coat at birth. Voles born in the autumn have thicker coats than those born in the spring and are better prepared for the winter period. Obviously, the thicker coat does not confer any immediate survival advantage but is advantageous for the growing pup.
Intrauterine Environment and IQ
The long standing and sometimes fierce ‘nature-versus-nurture’ controversy has often focused on the heritability of IQ, a fertile ground for infamous racist theories and ideologies. In order to arrive at meaningful and scientifically sound results, studies cannot be based on genetics only but need to take into account the different environments in which a human being and his/her IQ develop. Home, social groups, and educational frameworks are such environments, but so is the uterus. Devlin et al. [ 22 ] published a meta-analysis of 212 IQ studies which included over 50,000 twins. They reported that IQ is positively related to birth weight, normalized for gestational age, indicating that maternal nutrition may affect the IQ of the child. Moreover, they summarized literature reports indicating that IQ may also be increased by certain dietary supplements used by pregnant women and lowered by consumption of alcohol, drugs, and tobacco during pregnancy. Thus, the intrauterine environment affects the IQ in addition to the postnatal environment. The authors estimated, based on their studies, that the total effect of genes on IQ is less than 50%. Moreover, the fetal environment alone accounts for 20% of the covariance between twins and 5% between siblings born from the same mother at different times. The fluidity of the relative impact of the environment and genetics on IQ levels has been emphasized by Turkheimer et al. [ 23 ] who showed in close to 60,000 children that the relative contribution of the environment and genetics to future IQ levels is closely related to the socioeconomic status of the family. The lower the status, the higher the impact of the environment, and vice versa. According to this body of data it seems that in the low socioeconomic bracket virtually all of the variance of IQ is related to the pre-and postnatal environment while in the highest socioeconomic environment most of the IQ can be attributed to genetics.
Intrauterine Environment and Its Influence on Subsequent Sexuality
The development and determination of human sexual orientation is a complex and multicausal process and the ‘nurture-nature controversy’ has not spared human sexuality. For decades or even centuries, homosexuality has been regarded as an ‘acquired disease’. The notion was that homosexuality is either a voluntary deviation from ‘normalcy’ and therefore punishable by society or a disease and therefore amenable to treatment. Psychoanalysis as a treatment mode for homosexuality was developed by Sigmund Freud and advocated by psychologists and psychoanalytics until the 70s of the last century. This was based on the theory that the rejection of a dominant and overpowering father could cause homosexuality in his son. This ‘disease’ theory has been refuted only recently and the ‘nature’ origin of male homosexuality has gained ground. Numerous studies indicate that homosexuality, both in men and in women, may be familial, with genetic transmission accounting for a large proportion of the variance in sexual orientation. However, there may also be epigenetic events during fetal programming which are involved in the development of sexual orientation. Blanchard and Ellis [ 24 ] have suggested that the increased odds of homosexuality in later born males are related to the number of earlier born biological brothers and may be linked to a progressive immunization of some mothers to Y-linked minor histocompatibility antigens (H-Y antigens). It has been estimated that one in seven American male homosexuals is gay because of older brothers.
Fetal Programming as a‘Species Survival’Strategy
In a different dimension, fetal programming may also prepare the species for survival. In times of population stress such as famine, natural disasters such as after the Kobe earthquake, or man-made disasters, a reduction in the human sex ratio has been observed. Trivers and Willard [ 25 ] hypothesized that from the evolutionary point of view it would make sense to abort weak male fetuses who reproduce worse than weak daughters and thus allow the female to start a new pregnancy which may yield either a daughter or a more robust male fetus. This so-called Trivers-Willard effect (TWE) has been assessed recently in studies of the sex ratio among offspring of billionaires from Forbes Billionaires list [ 26 ]. As predicted by the TWE, in the highest economic brackets there is a significant sex ratio bias in favor of sons. Catalono and Bruckner [ 27 ] proposed their culled cohort hypothesis which states that maternal manipulation of the intrauterine environment would lead to selective abortion of fetuses based on their sex and robustness. They corroborated the TWE and showed in Swedish cohorts born between 1751 and 1912 that males who were born in years with a reduced male-to female ratio had a longer life span. Thus, in this context, fetal programming may present an extreme Darwinist mechanism of ‘selective feticide’ for the benefit of the fittest to survive a harsh environment.
The Fetus Affects Its Environment - Lessons Learned from Unlike Twin Pairs
Melamed et al. [ 28 ] retrospectively assessed 2,704 dichorionic twin pregnancies including 16.1% female-female (FF) pairs, 14.4% male-male (MM) pairs, and 69.5% female-male pairs (FM). The risk of preterm delivery was highest in the MM group, intermediate in the FM group, and lowest in the FF group. Female neonates from FM pregnancies had a rate of respiratory and neurologic morbidity similar to that of male infants and significantly higher than that of female neonates from FF pregnancies. In essence, we showed that it is better for a twin (male or female) to share the womb with a female rather than with a male co-twin. The effect of the male twin on his female co-twin has been attributed to transamniotic passage of fetal testosterone from the male twin to his sister in utero. In humans, this hypothesis has not yet been proven unequivocally.
Some Obstetrics Implications of Fetal Programming
Throughout history, folklore wisdom has had it that experiences of the pregnant woman would affect the unborn child. Hippocrates, almost 2,500 years ago, wrote about how the emotional state of a pregnant woman would influence the outcome of pregnancy. The ancient Greeks believed that looking at beauty during pregnancy would lead to the delivery of a beautiful child and looking at ugliness would lead to an ugly child. Paul-Murphy [ 29 ], in her remarkable book, points to the fact that few obstetricians seek information on depression and stress in pregnant women in spite of the fact that maternal depression occurs at least as often as pregnancy-induced hypertension and 5-10 times as often as gestational diabetes, both of which are checked in the course of prenatal care. Williams Obstetrics [ 30 ] has been the leading English textbook for decades. The 18th edition was published in 1989 and lists 13 causes of preterm labor, including ‘unknown causes’. Maternal stress and depression are not addressed as causes of preterm labor. In the 23rd edition [ 31 ] of this textbook, published 21 years later, four main direct reasons are cited for preterm labor and an additional paragraph elaborates on 11 antecedent and contributing factors. Among these an association with depression, anxiety, and chronic stress is mentioned but without further elaboration. The 10th edition of Danforth’s Obstetrics and Gynecology [ 32 ], published in 2008, does not mention prenatal maternal stress as a risk factor for premature delivery. Clearly, modern obstetrics has not yet fully integrated the understanding of various aspects of fetal programming with crucial pathologies, like preterm labor and delivery. Throughout pregnancy, the fetus is exposed to exogenous stimuli and substances which reach him through his mother’s body and he is extremely sensitive to theses stimuli. The nutrition of his mother during pregnancy will affect his health throughout life and so does her mental state. The intrauterine environment may affect his future sexuality. The intrauterine milieu has a strong impact on the fetuses’ subsequent cognitive ability, and Devlin et al. [ 22 ] believe that the impact of intrauterine life on subsequent intelligence equals or exceeds the impact of education. To acknowledge the principle of fetal programming means to acknowledge the fundamental importance of intrauterine life on future health and disease. This will have a profound impact on the definition of future prenatal care. Patient education, avoidance of toxins, adequate maternal nutrition, and physical activity may positively affect and change the direction of fetal programming. All of these and many more aspects will expand the definition of prenatal care from caring for the pregnant women to a new concept of preventive medicine for adulthood diseases. If so much is at stake during the fateful months of pregnancy for future health and well-being, then adequate resources need to be directed toward adequate prenatal care. Of course, one caveat needs to be voiced. Fetal programming should not be confused with fetal determinism and does not mean that at delivery the destiny of the newborn has been decided upon and that what is left is to follow a predetermined path to wherever it leads. Education, the postnatal environment, awareness about possible risk factors, and the appropriate means to meet them leave much of our destiny in our hands and in the hands of society at large. Understanding the concept of fetal programming means also identifying potential risks and trying to avoid them and dealing with the risk factors once they have been identified. In China, the age of a baby at birth is 1 year, meaning that the first year of life is counted as one instead of zero. Fetal programming is a new science reflecting the importance of this particular and fateful year for the rest of our life.
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Marek Glezerman, MD Department of Obstetrics and Gynecology Helen Schneider Hospital for Women, Rabin Medical Center IL-49100 Petah Tiqwa (Israel) Tel. +972 3 6952443, E-Mail m@glezerman.com
Social and Biological Determinants in Health and Disease
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Ambiguous Genitalia
Pierre D.E. Mouriquand a Justine M. Schober b
a Department of Pediatric Urology, Hôpital Mère-Enfants - Groupement Hospitalier Est, Bron, France; b Department of Urology, UPMC Hamot, Erie, Pa., USA
Developmental biology discoveries have advanced our understanding of anatomic details of the process and influences of genital formation. Although all malformations of the urinary and genital tracts are not yet explained by embryology, some malformations can be related to stages of development and hormonal or genetic factors. We continue to elucidate genes, proteins, and pathways related to sexual differentiation and organotypic features. Understanding the androgen and estrogen receptor status of genital tissue is critical to medical and surgical therapy considerations impacting the surface integrity of urogenital epithelium. Continuing elucidation of the embryology and immunohistochemistry of urogenital tissue may be a step toward the development of molecular tools to treat urogenital abnormalities. This chapter outlines the embryology, known causes, diagnostic categorization, and considerations for ambiguous genitalia.
Copyright © 2012 S. Karger AG, Basel
Sex Determination
Chromosomes, Embryology, Hormones, and Receptors
Sex differentiation can be divided into 3 phases. Chromosomal sex is established at fertilization. Male sex differentiation almost always occurs if a functioning sex-determining region of the Y chromosome (SRY) gene is present. Two functional X chromosomes are necessary for reproductive females. Deletions from Xp or Xq, or from both, have indicated that genes from both arms of the X chromosome are involved in ovarian differentiation and maturation. On Xq in the paracentromeric region there is a location for androgen receptor protein and for X inactivation. In female mammals this is important for dosage inactivation of one X chromosome. Random inactivation is fixed for each cell, and its progeny, so that each female is a mosaic of paternal and maternal active X chromosomes.
The second step is differentiation of the gonads. Development of the reproductive tract begins in the embryo and is sex independent. In the human, the embryonic period spans weeks 2-8 of gestation. Until the fetus reaches 50 mm in CR length (9 weeks), the genitalia in both sexes look identical. Germ cells appear in the epiblast and migrate through the primitive streak and then to the base of the allantois. Along the wall of the hindgut, they migrate to the urogenital ridge. In the primitive gonad, primitive sex cords displaying corticomedullary architecture are formed by the end of the 6th week. The third step is development of the phenotypic sex, comprising internal and external genitalia. It includes gonadal development. Testis formation starts with Sertoli cell proliferation and differentiation under the influence of SRY, which must reach a threshold level in a defined temporal window; otherwise, the ovary-determining pathway begins. Sertoli cells surround primitive germ cells and induce mitotic arrest. The formation of testis cords from the medullary region of the primitive sex cord is the first visible sign of male differentiation. From the 6th to the 12th week, the organotypic patterns of the testis are established. Proliferation of Sertoli cells leads to the characteristic enlargement of the early testis. The number of Sertoli cells appears to be closely related to the number of germ cells, testicular size, and sperm count in later life. During the evaluation of a newborn with ambiguous genitalia, small gonads can indicate gonadal dysgenesis. Later, this finding may explain a delayed onset of puberty or male subfertility.
Vascularization of the testis starts with formation of a large artery under the coelomic surface. The coelomic vessel is formed following SRY expression, with a role for androgen transport suggested. Later, anastomoses to the arteria ductus deferentis and arteria cremasterica are formed, and the blood-testis barrier is created by the Sertoli cells. The tunica albuginea comprises mesenchymal tissue forming a thick fibrous capsule. It is a specialized structure in both sexes. In the male, it forms the testicular septations and the mediastinum testis. It is involved in the compartmentalization of the testis, and laminin deposition can be demonstrated at early stages. The tunica contains contractile elements. It promotes the transport of spermatozoa in adult life, maintains the interstitial pressure, and controls testicular blood flow.
The tunica albuginea of the ovary appears to have a regulatory role in the maintenance of the germ cells. The tunica of the testis is thicker than that of the ovary. In newborn boys, the tunica is white or bluish, in newborn girls it is yellow or brown, and follicular cysts can be seen.
Local androgen action is required for the differentiation of the epididymis and the vas.
Ovarian formation starts in the early fetal stage, described by Jirasek [ 1 ] as extending from the end of the embryonic period (the first week) until week 16 of gestation. During the first week, oogonia at the center of the gonad enter meiosis which rapidly extends peripherally to reach oogonia at the surface of the ovary. Two X chromosomes are not needed at this point. After 16 weeks, primary follicles begin to form in the ovary and are characterized by an oocyte. These are completely surrounded by a single layer of follicular cells and connective tissue. If the surround is incomplete, oocytes degenerate. Formation of primary follicles requires two X chromosomes. At the age of viability (24 weeks) some ovarian follicles consist of growing oocytes surrounded by several layers of granulosa cells. Stroma surrounding the growing follicles organizes itself into theca interna and externa. At the end of gestation some follicles become vesicular, degenerate, and disappear from the ovary within 6 months of birth. They present again at the onset of puberty. They constitute an organotypic pattern and are considered indicators of the presence of germ cells. Absence of germ cells is compatible with testicular development, but without germ cells ovary development does not take place and a streak gonad will result.
The gubernaculum and the suspensory ligaments are relevant for the position of the gonad. Incomplete regression of the caudal suspensory ligament may contribute to the abdominal position of the gonads in some patients with XY disorders of sex development (DSD). In newborns with ambiguous genitalia, ultrasound of the inguinal region and the lower abdomen is the first step. If no gonad is found, laparoscopy should be considered.
Reproductive Ducts
Mesonephric and Paramesonephric Ducts
Male differentiation of the mesonephric duct occurs in response to testosterone secreted locally by the ipsilateral testis. At the 7th week, developments are seen to diverge between the sexes. Sequential expression of many genes during formation of the epididymis, vas deferens, and seminal vesicle is involved. Secretion of the glycoprotein MIS by Sertoli cells leads to regression of the Müllerian ducts. Incomplete regression occurs in some types of DSD, leading to vaginal remnants or utricular cysts. In the female fetus, organogenesis involves regression of the mesonephric ducts as well as stabilization of the paramesonephric ducts. This proceeds in the absence of testicular hormones. At the time of apparent male differentiation in an XY fetus, the comparable undifferentiated structures in the female are irreversibly committed to female organogenesis. At the end of the embryonic period, fusion of the caudal ends of the two paramesonephric ducts with the urorectal septum occurs, forming the uterus (at about 63 days of gestation). The cephalic ends develop fimbriae, the lower segment, and the uterine tube, with transverse lie established by descent of the ovary. The genital canal is established at about 80 days with absorption of the median septum. It lengthens, and its caudal end continues to grow and contacts the posterior wall of the urogenital sinus. With additional cellular proliferation, the vagina is formed. The cervix (caudal two thirds of the fetal uterus) may be of either paramesonephric or urogenital sinus origin [ 2 ]. The uterus and vagina can be visualized by ultrasound, and the cervix can be seen by genitoscopy postnatally. In the case of a girl with an inguinal hernia containing an ovary, genitoscopy has been suggested to rule out androgen insensivity syndromes.
Development of the External Genitalia
The initial signs of masculinization are an increased distance between the anus and genital structures. Circulating androgens, and conversion to dihydrotestosterone (DHT), induce genital tubercle (GT) growth. Tubularization of the urethral plate leads to formation of the urethra and is important for the development of corpus spongiosum and other penile structures. The fossa navicularis forms independently (ectodermal ingrowth is debated). Differentiation of the external genitalia starts at 8 weeks, the coronal sulcus separates the glans and penile shaft by 12 weeks, and the glandular urethra forms by 16 weeks. The prepuce is formed following ventral closure of the glans, and separation of skin folds from the glans is not complete until birth. Involved genes, proteins, and pathways are SHH, FGFs, BMPs, and androgen/androgen receptor.
The scrotum is formed by fusion of the labioscrotal folds under androgen action, leaving a visible raphe. Normal scrotal insertion of the gubernaculum testis is essential for the inguino-scrotal phase of the descensus. The posterior aspect of the testis is not normally covered by the processus vaginalis and is fixed to the scrotal skin. Between 63 and 77 days, feminization or differentiation from the masculinized form begins. The phallus does not lengthen but bends forward or caudally. Before 20 weeks, there is a slow phase of growth of the genital swellings that cover superior and lateral aspects of the clitoris. The anogenital distance does not change, but the phallic portion of the urogenital sinus remains open, and genital folds do not fuse. At 14-20 weeks, the vagina opens into the pelvic portion of the urogenital sinus and it becomes the vaginal vestibule. After fetal ovarian follicular growth (20-22 weeks), there is rapid ventral outgrowth of the perineum, the urethral and vaginal openings separate, and the urethra is brought to the surface. The clitoris becomes incorporated into the fused anterior ends of the genital folds (labia minora), which continue to grow posteriorly. Genital swellings lateral to the labia minora become the labia majora, anteriorly continuous as the mons pubis. The growth of the labia minora is greater than that of the labia majora; they are seen protruding out of the labia majora at 23-25 weeks of gestation. After 26 weeks, the labia majora have grown sufficiently to cover the labia minora [ 1 , 2 ]. At midtrimester there is no difference in the distribution of androgen receptors between male and female fetuses in the external genitalia; estrogen receptors are present only in the genitalia of the female fetus. It is not known when estrogen receptors appear or what induces their appearance. Their lack may be what protects male fetuses from the effects of maternal estrogen.
Development of a bladder and urethra separate from the vagina requires the growth of a membrane from the cranial to the caudal region in the urogenital sinus. Anomalies of female embryogenesis during this process lead to a variety of clinically recognized disorders. Estrogen is responsible for the vascularity and thickness of vaginal tissue. Failure of the labia to fuse in the normal female fetus may be due in part to the lack of fetal androgen production and low 5-α reductase activity (and in part to maternal estrogen stimulation of ER-positive urethral folds), causing the labia minora to diverge laterally. There is extensive circumstantial evidence that 17β-estradiol and progesterone influence the postnatal physiology of extragenital and especially genital (vulval) skin in the human female.
Molecular Biology
The AR protein is a member of the steroid hormone-activated transcription regulator family, a subset of the superfamily of ligand-dependent transcription factors. Receptors such as estrogen receptor-α (ER-α) and ER-β, mineralocorticoid receptors, glucocorticoid receptors, and progesterone receptors affect transcription through steroid hormone-receptor interaction. The AR protein, like other steroid hormone receptors, consists of three functional domains. The carboxy-terminal (ligand-binding domain) is responsible for androgen binding, the central domain accounts for DNA binding (DNA-binding domain), and the amino-terminal plays a role in transcriptional activation. Together, the three functional domains determine the ability of androgen-AR interactions to regulate transcription. The AR protein is encoded by 8 exons in a single gene located on Xq 11-12. The most frequently seen mutations are nonsense or missense point mutations, with clusters of mutations seen on exons 5 and 7 which code for the ligand-binding domain of the AR. Mutations of the AR gene result in abnormal AR protein binding capabilities which leads to an inability of androgen hormones such as testosterone and DHT to properly regulate transcription. Defects in androgen-AR protein binding directly affect the development of urogenital mesenchyme into male or female external genitalia in 46, XY genotypical males [ 3 ].
The role of androgens in sexual differentiation was first elucidated in 1940 by Jost [ 2 ] who concluded that the testes were responsible for external genital differentiation through secretion of androgens. Recent studies have shown that androgen-related effects in a cell or tissue may be regulated through paracrine signaling by neighboring cells. In male genital differentiation in particular, the prostate demonstrates mesenchymal (stromal)-epithelial interactions that appear to be an integral part of the epithelium’s differentiation into characteristic branched ducts of the prostate. Steroid hormones such as 17β-estradiol and progesterone are capable of altering epithelial proliferation and organization through paracrine signaling of stromal cells. This paracrine signaling appears to be influenced by steroid-steroid hormone receptor interaction in the nearby cells.
There is also evidence that androgens have direct, non-AR-regulated effects on cells. Direct intracellular response to androgens can occur quickly, within seconds to minutes. This so-called ‘nonclassical’ androgen response pathway can involve several mechanisms such as activation of sex hormone-binding globulin receptors, activation of phosphatidylinositol 3-OH kinase (PI3-K) signaling, and modulation of voltage-and ligand-gated ion channels and transporters. The idea that the role of AR extends beyond the classic androgen-AR mechanism of transcription regulation is intriguing in partial androgen insensitivity syndrome (PAIS). It is possible the varied phenotypical presentations seen in PAIS are in part related to other cellular signaling roles separate from AR that androgens play in genital differentiation.
Classification of Ambiguous Genitalia
Chromosomal Disorders
Sex Reversal, Turner’s Syndrome, True Hemaphroditism, Mosaics, Mixed Gonadal Dysgenesis, and Pure Gonadal Dysgenesis. 46, XY sex reversal is a DSD resulting in individuals of the 46, XY genotype with female phenotypic characteristics or ambiguous genitalia and associated complete gonadal dysgenesis in ~1/20,000 births. The commitment of undifferentiated gonads to testes initiates the development into the male phenotype in normal 46, XY males. The Y chromosome has long been thought to carry the testis-determining factor (TDF). In the absence of the Y chromosome, such as in 46, XX normal females or 45, X Turner’s syndrome, the individuals are phenotypically female. The SRY is located at Yp11.3 and it was hoped that the discovery of SRY would lead to a rapid expansion of knowledge regarding early sex determination. However, SRY as the only TDF was shown to be a gross oversimplification. Many other genes active in sex differentiation have been confirmed, including genes coding for transcription factors such as SOX9 [Sry-type high-mobility group (HMG) box 9], DMTR1, GATA4, DAX1, SF1, WT1, LHX9, and DSS and signaling molecules antimullerian hormone (AMH), WNT4, FGF9, and DHH. Genes coding for the male phenotype have been found on X chromosomes (e.g. DSS) and autosomes 9, 10, and 17 (e.g. DMTR1).
Genetic mutations at the distal end of the short arm of chromosome 9 have been demonstrated in cases of 46, XY sex reversal. Namely, doublesex and MAB-3 related transcription factors 1 (DMRT1) and 2 (DMRT2) are mapped to band 9p24.3. DMRT1 appears to play a role in early sex differentiation while the role of DMRT2 is in somitogenesis. Genetic mutations at the distal 9p locus are typically de novo, resulting from deletions at 9p more often than point mutations. The shortest deletion at 9p still results in the loss of both DMRT1 and DMRT2, allowing for the possibility of both playing a role in early sex determination. This may also account for multiple phenotypic anomalies seen in association with XY sex reversal in certain individuals with 9p mutations. Individuals with 9p mutations and XY sex reversal have been observed to display abnormal facies, hypotonia, and cardiac and gastrointestinal defects, as well as mental and motor developmental delay.
Overvirilized Females
Fetal Sources and Congenital Adrenal Hyperplasia
Genital masculinization in a chromosomally normal (XX) female infant, consisting of clitoromegaly and various degrees of vaginal abnormality, may result from congenital adrenal hyperplasia (CAH). This DSD has a prevalence of 1 in 15,000 births worldwide and is associated with a deficiency in 21-hydroxylase. Consequent virilization occurs because the external genitalia are competent to respond to DHT. The milder enzyme deficiency, i.e. nonclassical 21-hydroxylase deficiency (NC21OHD), was found to be the most common autosomal recessive disorder in humans. The disease frequency of NC21OHD varies between ethnic groups, with the highest ethnic-specific disease frequency in Ashkenazi Jews (1 in 27). NC21OHD is diagnosed based on serum elevations of 17-OHP and confirmed with molecular genetic analysis. Females with ‘classical’ 21 - OHD are exposed to excess androgens prenatally and are born with virilized external genitalia. Potentially lethal adrenal insufficiency is characteristic of two thirds to three quarters of patients with the classical salt-wasting form of 21-OHD. Non-salt-wasting 21-OHD may be diagnosed based on genital ambiguity in affected females, and/or later on the occurrence of androgen excess in both sexes. Another CAH variant, p450 oxidoreductase deficiency may also result in ambiguous genitalia [ 4 – 7 ].
Maternal or Exogenous Sources of Androgens
Other sources of masculinization with resultant ambiguous genitalia are androgenic stimulation of the fetus in utero from nonfetal sources. Fetal virilization occurs during a critical period between weeks 8 and 13 of gestation and results in labioscrotal fusion and urogenital sinus formation. Female embryos have the same androgen receptor system in the urogenital tract as male embryos; therefore, administration of androgens at the appropriate time during embryogenesis may cause profound masculinization. Internal genitalia are not masculinized and wolffian duct remnants are normal.
Although CAH is the most common cause of masculinization in the female fetus, masculinization as a consequence of a maternal hormone-producing tumor is becoming a more frequently recognized clinical entity (luteoma of pregnancy, granulosa tumor, arrhenoblastoma, hilar cell tumor, lipoid cell tumor, masculinizing ovarian stromal cell tumor). Other masculinizing tumors which are maternal sources of androgens inducing virilization include: Krukenberg tumor, adrenocortical carcinoma, adrenal myelolipoma, ganglioneuroma, choriocarcinoma, testosterone-secreting adrenal adenoma, and placental site trophoblastic tumor. Bilaterality and multinodularity are more common in luteomas than in these other tumors. Polycystic ovary syndrome and massive ovarian edema are also described as a sporadic cause of virilization during pregnancy.
Maternal ingestion of androgens, progestagens, and drugs such as danazol, stilboestrol, and 1-9-nortestosterone (for threatened abortion) may cause labial posterior fusion, clitoromegaly, and more pronounced virilization. Ingestion of the off-label ‘appetite stimulant’ cyproheptadine and methandienone (a derivative of testosterone) has been cited as a source of fetal virilization. Maternal application of topical preparations, and exposures noted to induce virilization of the female fetus include: cutaneous androgen preparations, methandrostenolone-containing cream for eczema, and exposure to the fungicide vinclozolin. Only 65% of masculinized mothers deliver masculinized female infants. Protective mechanisms such as active placental aromatization of androgens into estrogens, maternal metabolism of androgens, increases in androgen-binding proteins (SBP and SHBG) under the influence of placental estrogens, and the protective buffering effect of the high concentrations of estrogens found in fetal blood might be responsible for the protection of the fetus against masculinization.
Undervirilized Males
In 46, XY patients, hypospadiac penis and micropenis are the two main presentations of the undervirilized male. Hypospadias is a result of a development halt of the ventral aspect of the GT during the first term of gestation. A micropenis is a small fully formed GT. Both anomalies are classified as DSD which encompass all congenital genital anomalies and their potential cerebral imprinting. Several epidemiological studies have shown a trend of increased incidence of GT anomalies. Hypospadias incidence is in the vicinity of 1 in 250 male births, with marked variations between countries. The incidence of micropenis is unknown. Causes of hypospadias are essentially unknown and most likely multiple. Four main avenues currently explain faulty development of the GT: (1) genes, gonads, hormonal production, and target tissues; (2) placental hormonal machinery, especially during early gestation; (3) the mother (main biological supervisor), and (4) the maternal environment during gestation [ 8 ].
Genetic Causes
Family cases of hypospadias are well reported, with percentages varying between 10 and 25%. The risk of having another boy with hypospadias in a family with one case is increased 17-fold compared to controls [ 9 ]. Many genes have been reported in association with abnormal genital construction: those involved in GT development (HOX, FGF, ATF3, CXorf6, etc.), those involved in gonadal determination and testicular development (WT1, SF1, SOX9, DMRT1, DAX1, WNT4, etc.), those involved in androgen synthesis located in Leydig cells, and those involved in androgen action on target tissues (5-α reductase) [ 8 ].
Chromosomal anomalies are found in 7% of patients with isolated hypospadias, more frequently if other genital anomalies are associated. Several well-identified syndromes may associate an abnormal GT: Klinefelter syndrome (47,XXY), mixed gonadal dysgenesis (45, X0/46, XY), 46, XX males with or without a detectable SRY gene, and ovotesticular DSD (46, XX in 60% cases and 46, XY/46, XX in 40%) [ 10 , 11 ].
Hormonal Failures
Hormonal failure can be due to insufficient production (gonadal dysgenesis), failed central regulation, or an abnormal response of the target tissue. Evaluation of hormonal secretion varies with the age of the child; on the first day of life, the male newborn plasma androgens are still high due to placental stimulation but will soon fall before the so-called ‘mini puberty’ (days 15-90) where a flare of sexual hormones occurs secondary to gonadotropin stimulation. Beyond the 3rd month of life, androgens are low and will remain so until puberty; AMH and inhibin B (both secreted by the Sertoli cells) are high and represent reliable indicators of Sertoli cells. Leydig cells can be challenged by injections of human chorionic gonadotropin (HCG) or its synthetic recombinant analogs [ 12 ]. Plasma AMH above 600 pmol/l is considered a normal value. There is a consensual protocol for HCG stimulation. Failed hormonal gonadal secretions are commonly labeled as ‘gonadal dysgenesis’, although there is no clear histological definition of this entity [ 13 ]. Tissue response to androgens can be assessed by clinical changes after hormonal stimulation and by sequencing the genes of the androgen receptors. Beyond these receptors, tissue proteins play an important role in GT construction and can be unbalanced as shown on the ventral aspect of the hypospadiac penis.
Placental Dysfunction
Low-weight newborns, twins, and very young or ‘old’ mothers represent significant risk factors for abnormal GT. In these circumstances, the placenta may be deficient and may not provide an adequate hormonal climate for the development of the GT. Assessment of placental function is actually mainly represented by the measurement of HCG levels in the mother’s plasma, which is a rough indicator [ 14 ].
The Mother
Given that it is a reference system for biological homeostasis, any disorder of the mother’s hormonal status (hormonal treatment, tumors) may affect the fetus’ hormonal balance and the construction of the GT [ 15 ]. Couples with low fertility requiring intracytoplasmic sperm injection or IVF are at risk for the production of a fetus with a higher risk of genital anomalies [ 16 ].
The Environment
Any environmental hormonal disruptors or promoters during pregnancy [ 17 ], or even perhaps before, may affect GT development [ 18 , 19 ]. It is speculated that chemicals such as xenoestrogens (fertilizers, polystyrenes, etc.), estrogen-like molecules, and environmental antiandrogens may have a role in the increasing frequency of these anomalies as well as in the increasing number of undescended testes, testicular cancer, and sperm count deterioration [ 20 , 21 ].
Anatomical Aspects of the Insufficiently Developed Genital Tubercle
Micropenis can be related to failed central hormonal stimulation such has gonadotrophic stimulation or GH stimulation. It can also be the consequence of a poor tissue response (5-α reductase deficiency; partial androgen insensitivity) [ 22 ]. Hypospadias is classically represented by the association of a ventrally bent GT, a ventral opening of the urethra at any place between the glans and the perineum, and abnormal distribution of the penile skin. It is the result of a development halt of the tissues forming the ventral aspect of the penis. As a result, the corpus spongiosum, which normally surrounds the urethra, divides creating a ventral triangular defect whose summit is the division of the spongiosum; the lateral sides are the atretic pillars of spongiosum reaching the glans wings, and the open glans forms its base. All of the tissue in this triangle is poorly developed, leading to the ventral curvature of the penis and the poorly formed urethra. Most hypospadias classifications are wrongly based on only the position of the urethral meatus. The GT anomaly is far more complex and its severity must include the size of the GT, the glans, the length of the defective urethra, the quality of the tissues forming the urethral plate, and, moreover, the level of division of the corpus spongiosum. Accurate identification of GT development can only be established in the operating room, once the GT has been fully degloved. One can then distinguish hypospadias with a proximal division of the corpus spongiosum, which are associated with a ventral curvature, from those with a distal division of the corpus spongiosum, which have little or no curvature.
A micropenis is a fully formed GT with a size under 25 mm in length (or under 2-2.5 SD) during the first year of life. It must be distinguished from the buried GT which has a normal size but a significant skin shaft shortage, and from the webbed penis which is the abnormal anchorage of the scrotal skin onto the ventral aspect of the penis [ 23 ].
Most deficient GT are diagnosed at birth or in the first few months of life. It is possible to identify some of the most severe anomalies during the prenatal period. Most GT anomalies are straightforward. Conversely, severely hypovirilized GT, in association with other genital anomalies (undescended testes, large mullerian cavity) and discrepancy between the genital aspect and the karyotype, may raise difficult discussions regarding the choice of gender (gender assignment) [ 24 – 26 ]. These rare situations should involve an experienced multidisciplinary team including endocrinologists, geneticists, molecular biologists, psychologists, pediatric urologists, grown-up patients, and, of course, the parents. It is amazing that, at the dawn of the third millennium, one still does not know what makes a boy a boy and a girl a girl. Observational medicine of multiple, and individual, clinical cases is the only tool we have to build the foundations of an approach to the most complex cases. We have learned from these observations that the status of chromosomes, hormones, gonads, the phallus, the vagina, etc., are not sufficient to define a boy or a girl [ 27 ]. National and international meetings and think tanks such as the Chicago Consensus Meeting (2005) and EuroDSD have encouraged the exchange of ideas, data bases, research programs, and publications [ 28 ].
Sexual Identities
Understanding of and decision making for a child in the neonatal period with severely abnormal genitalia is an extraordinary challenge. It is quite paradoxical to opt for a gender without consulting the patient himself or herself. This process has been highly criticized by some patients and patient advocacy associations and remains quite controversial. To understand the complexity of these situations, one could distinguish three different identities. Individual sex identity, which is what the individual thinks he or she is, is quite a subtle spectrum and will be shaped by growth and external and internal influences. Behavioral identity, which is the individual’s erotic inclination, will also form with time. Both of these identities are invisible in the neonatal period. The last identity, i.e. social identity, (or gender) is how society looks at the individual and recognizes the individual as male or female. Social/gender identity is far more rigid, and less subtle, than the others. It is the way the social mirror reflects the individual’s image, i.e. the way to make the individual visible. It is the only tangible identity at birth.
Decision Tools
A newborn with undefined sex is moral torture for parents who cannot present a gendered child to the family. It is therefore a matter of relative urgency to choose a gender which will render this child visible to society. Four factors influence the choice of gender: (1) internal sex, represented by the child’s genetic, gonadal, and hormonal profiles; (2) external sex, which is the appearance of the genitalia, and more specifically the size of the GT and the possible presence of a retrourethral müllerian cavity; (3) functional sex, which comprises the potential future fertility and the capacity of having intercourse as a male or a female, and (4) social sex, which refers to the cultural medium where the child will grow. The mother’s deep feelings are of utmost importance in this decision-making process [ 29 ].
Hormonal Treatments
Steroid treatments are mainly based on androgen stimulation to enlarge the penis. There is no consensual protocol on if, when, and how to stimulate GT growth. There are three main possibilities: systemic testosterone (testosterone enanthate), topical DHT, and HCG (human or recombinant). When the GT is under 25 mm in length and 15 mm in width during the first year of life, androgen stimulation is commonly used. Some adverse effects, such as bone growth, should be monitored. It is also acknowledged that androgen treatments might be deleterious to the healing process after reconstructive surgery [ 30 ]. A 3-to 6-month gap between stimulation and surgery is recommended. Androgens mainly act on the growth of the GT dorsum and the ventral segment situated proximal to the division of the corpus spongiosum. Tissues located beyond the division of the corpus spongiosum are likely less androgen sensitive. These dysplastic tissues solely used in hypospadias reconstruction may not grow as well as the rest of the penis. This would explain the late urethral inadequacy with some techniques (Duplay, tubularized incised plate). Some surgeons favor the use of dorsal tissues for urethroplasties (onlay urethroplasty) which have a normal response to androgen stimulation.
Masculinization Surgery
DSD surgery should be done by DSD surgeons, i.e. surgeons familiar with genital reconstruction in children. Hypospadias reconstruction is commonly performed between 6 months and 2 years of age and includes three main steps. The first step is full dissection of the GT to expose the level of division of the corpus spongiosum which is the proximal landmark of the GT anomaly. It is then possible to evaluate the quality of the tissues available and choose the most appropriate technique for urethroplasty. In the second step, the choice of urethroplasty is dependent upon the length of the urethra to reconstruct, the quality of the urethral plate, the size of the glans, and the availability of dorsal tissues. The third step consists of refashioning the ventral aspect of the GT by redistributing the tissues around the penis, with or without conservation of the foreskin. There is no universal technique for hypospadias repair and no gold standard technique. The outcome is dependent upon many factors, the most important of which is the experience of the surgical team and the quality of postoperative care.
Phalloplasty is even more challenging and has been imported from adult urological surgeons experienced with transsexual surgery. Experience and follow-up in children is extremely short and these procedures should be confined to one or two places on each continent. Main indications are represented by aphallia, a very small GT in males, or a damaged penis after exstrophy surgery [ 31 ].
Feminization Surgery
Feminization surgery is the ultimate alternative in patients carrying Y material. This surgery was common in the past in groups of patients with severe genital ambiguities for whom female assignment was the usual ‘by default’ response. The rationale was that it is surgically easier to create a penetrative conduit than a penetrating organ. Nowadays this option is much rarer even in mixed gonadal dysgenesis patients. The remaining indications are essentially represented by the complete androgen insensitivity syndrome, extreme forms of micropenis or PAIS with poor response to androgen stimulation, 5-α reductase deficiency, 17-hydroxysteroid dehydrogenase deficiency, LH receptor deficiency, and complete gonadal dysgenesis.
This surgery includes three main steps. The first step involves creation of a vaginal conduit by connecting an existing müllerian cavity to the pelvic floor, or by dilating an existing vaginal cup, or by creating a penetrative conduit de novo. There is no consensus regarding the timing of this surgery. The second step consists of GT reduction which is also subject to controversies as this surgery may jeopardize GT sensitivity. A better understanding of the nerve distribution of the GT has led to major changes in the surgical procedures (a paradox of this surgery is that outcomes will be assessed many years in the future, when the patient becomes an adult). The third step is refashioning the perineal anatomy.
Other procedures essentially include gonadal surgery and surgery of the müllerian remnants.
The Gonads
Abnormally formed gonads are at risk of developing malignancies. This risk varies with the nature of the DSD. The highest risks are mostly of mixed gonadal dysgenesis, pure gonadal dysgenesis, and Frasier and Drash syndromes. The tumor, when it arises, develops from the testicular contingent of the gonads [ 32 ]. These abnormal gonads can be either brought down into the scrotum to allow close follow-up or removed. Many patients will require some form of hormonal supplementation at the age of puberty and beyond if gonadectomy is elected.
Uterine Remnants
Removing uterine remnants is advisable when the male gender is assigned as they may start bleeding at puberty with the influence of aromatase conversion of steroid hormones. Removing utricular cavities is sometimes necessary if the patient becomes symptomatic (dysuria, urinary tract infection). This surgery is usually performed laparoscopically, with special attention to the vasa deferentia, which are often closely attached to the utricular walls.
Results of Surgery
Results of masculinization surgery are evaluated according to the cosmetic aspects of the reconstructed GT, and its function, in terms of both transurethral urinary flow and sexual performance. It therefore requires a very long follow-up, through childhood, puberty, and adulthood. It is actually very difficult to get an objective idea of the results of the surgery because patients’ views often differ from surgeons’ views. Urine flow studies are unreliable because the material used for replacing the deficient urethra is different from normal urethral walls and because patients who received urethral surgery, especially children, commonly have dys-synergic micturition for a long time postoperatively. The capacity of children to tolerate dysuria is remarkable, and it is enhanced by the fear of having to undergo another surgical operation. Absence of a urinary tract infection and complete bladder emptying, checked by ultrasound scans, with no deterioration of the whole urinary tract, are probably the most reassuring criteria to assess the outcome of these reconstructions. The reported results on sexual life after early surgery are scarce and subjective. Questions remain about the sensitivity of the glans after hypospadias or clitoral surgery [ 7 ]. The number of operations certainly affects the patient’s confidence to enter adult sexual life. Ejaculatory anomalies are variable between 6 and 37% of operated individuals. There is no convincing data on impaired fertility.
Virilization of the female genitalia may vary widely in severity. Simple clitoromegaly or very distal entrance of the vagina into the urogenital sinus may require no treatment. Issues of an appearance of gender typicality have been debated for parent and patient concerns, with the risk for genital sensory function weighed against cosmesis. Timing, staging, and separating clitoroplasty and vaginoplasty (allowing patient input and decreasing unwanted surgery and revisions) continue to be at issue. In more virilized forms (as the vagina enters the urogenital sinus more proximally and nearer the bladder neck), typical intercourse may be impossible. Reconstructive surgery may be necessary to establish sexual capability. Feminizing genitoplasty may require multiple revision surgeries; 50-79% of patients require a second procedure. Third and fourth procedures are not uncommon for adequate vaginal construction which allows intercourse. As the procedure is not assuredly successful, only 77% of those who had this surgery ultimately have an adequate vaginal introitus on long-term follow-up. Scarring at the introitus or of the entire vaginal segment has been a problem. This complication is most prevalent when local skin flaps and squamous epithelial grafts are used to create portions of the vagina and in some cases the entire vagina (neovagina) [ 5 , 6 ].
Outcome of Micropenis
Here again, data are rare and reported series are short. Patients seemed to be satisfied with their sex of rearing, although they complained about the size of their penis with regard to the ability to urinate and direct the stream, appearance in the changing room, and during vaginal intercourse. Other studies do not report any major concerns and do report a rather good quality of life [ 33 , 34 ].
Outcome of Phalloplasty
Present data only concerns adult patients. A lot more detailed information concerning child and adolescent outcomes needs to be discovered in this very specific group.
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24 Bin-Abbas B, Conte FA, Grumbach MM, Kaplan SL.: Congenital hypogonadotropic hypogonadism and micropenis: effect of testosterone treatment on adult penile size why sex reversal is not indicated. J Pediatr 1999;134:579–583.
25 Meyer-Bahlburg HF: Gender identity outcome in female-raised 46, XY persons with penile agenesis, cloacal exstrophy of the bladder, or penile ablation. Arch Sex Behav 2005;34:423–438.
26 Reiner WG, Kropp BP: A 7-year experience of genetic males with severe phallic inadequacy assigned female. J Urol 2004;172:2395–2398, discussion 2398.
27 Reilly JM, Woodhouse CR: Small penis and the male sexual role. J Urol 1989;142:569–571, discussion 572.
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29 Cheikhelard A, Gapani C, Catti M, et al: Potential determinant factors of sexual identity in ambiguous genitalia. J Pediatr Urol 2005;1:383–388.
30 Gorduza DB, et al: Does androgen stimulation prior to hypospadias surgery increase the rate of healing complications? A preliminary report. J Pediatr Urol 2011;7:158–161.
31 Lumen N, Monstrey S, Selvaggi G, Ceulemans P, De Cuypere G, Van Laecke E, Hoebeke P: Phalloplasty: a valuable treatment for males with penile insufficiency. Urology 2008;71:272–276, discussion 276-277.
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33 Mazur T: Gender dysphoria and gender change in androgen insensitivity or micropenis. Arch Sex Behav 2005;34:411–421.
34 Husmann DA: The androgen insensitive micropenis: long-term follow-up into adulthood. J Pediatr Endocrinol Metab 2004;17:1037–1041.
Justine M. Schober, MD, FAAP Department of Urology, UPMC Hamot 333 State Street, Suite 201 Erie, PA 16507 (USA) Tel. +1 814 455 5900, E-Mail schobermd@aol.com
Central Nervous System and Clinical Applications
Section Editor

Donald W. Pfaff, PhD
Department of Neurobiology and Behavior
The Rockefeller University
New York, N.Y., USA
Central Nervous System and Clinical Applications
Schenck-Gustafsson K, DeCola PR, Pfaff DW, Pisetsky DS (eds): Handbook of Clinical Gender Medicine. Basel, Karger, 2012, pp 70–81
Chronic Stress and Allostatic Load
Robert-Paul Juster Sonia J. Lupien
Center for Studies on Human Stress, Fernand-Seguin Research Center, Louis-H. Lafontaine Hospital, Montreal, Que., Canada
The biopsychosocial signatures for stress-related conditions are age, sex, and gender specific. The trajectories of these diseases are furthermore dynamic as they manifest themselves differently throughout lifespan development and in the context of broader social, cultural, and historical factors. Delineating the effects of chronic stress on the brain and body therefore requires approaches that capture the complexities of the predetermined sex of the individual and the acquired gender throughout the life cycle.Targeting these complex risk factors and promoting protective factors can advance person-centered approaches in medicine. With the goal of refining the diagnosis, treatment, and prevention of diverse diseases, this chapter presents recent progress recorded in the literature on stress-related diseases, highlighting the allostatic load model that represents the biological damage individuals incur when chronically stressed.
Copyright © 2012 S. Karger AG, Basel
Stress is broadly defined as a real or interpreted threat to an individual’s physiological and psychological integrity that results in biological and behavioral responses [ 1 ]. While acute stress is healthy, chronic stress is a major risk factor for many conditions discussed in this textbook. By focusing on nuances stemming from age, sex, and gender, this chapter will introduce the reader to advances in measuring chronic stress using the allostatic load (AL) model [ 2 ].
The Measurement of Stress
The magnitude of stress experienced by an individual can be assessed by measures of environmental stressor frequencies, subjective psychological ratings, and/or objective biological indices related to stress responses. Situations that are novel or unpredictable, threaten self-preservation, and/or diminish one’s sense of control will additively contribute to stress responses [ 3 , 4 ]. This response refers to the sympathetic-adrenal-medullary axis release of catecholamines within seconds and the hypothalamic-pituitary-adrenal axis secretion of glucocorticoids several minutes thereafter. Resulting stress hormones like adrenalin and cortisol mobilize the energy necessary for fight-or-flight responses first described by Walter Cannon.
According to Sterling and Eyer [ 5 ], this metabolic allocation of catabolic energy exemplifies allostasis, defined as the biological processes that facilitate dynamic stabilization to environmental demands. The price the brain and body pay for cumulatively generating allostatic responses is called AL [ 2 ], referring to the multisystemic biological damage caused by chronic stress. As this chapter will reveal, AL is easily measurable using indices that currently incorporate various peripheral biomarkers. These are related to older age, distributed differently according to sex, and moderated by gendered risk factors and protective factors discussed in our chapter’s later sections.
Clinical Aspects
Neurological Regulation and Allostatic Load
The brain is central to allostasis and AL. Stress hormones bypass the blood-brain barrier to bind to three key receptor-dense regions: the prefrontal cortex, the amygdala, and the hippocampus. Chronic production of cortisol is believed to be neurotoxic, leading to frontal lobe malfunctioning, amygdaloidal hypertrophy, and hippocampal atrophy associated with region-specific cognitive impairments and emotional dysregulations throughout the life cycle [ 6 ]. Furthermore, individual differences in constitutional (e.g. genetics, development, and experience), behavioral (e.g. coping and health habits), and historical (e.g. trauma/abuse, major life events, and stressful environments) factors also modulate an individual’s sensitivity to chronic stress that can further damage the brain and body. Of critical importance is the timing and duration at which major stressors and/or traumas are experienced, as this will profoundly affect neurological development that, in turn, can exacerbate the inherent vulnerabilities conferred onto individuals.
Life Cycle Model of Stress
Lupien et al. [ 6 ] recently proposed that the consequences of chronic stress and/or trauma at different life stages depend on which brain regions are developing or declining at the time of the exposure. As illustrated in figure 1 , stress in the prenatal period affects the development of the hippocampus, prefrontal cortex, and amygdala, leading to programming effects. The differential effects of postnatal stress differ according to environmental exposure; for instance, maternal separation during childhood generally leads to increased secretion of cortisol, whereas exposure to severe abuse is associated with decreased levels of cortisol. From the prenatal period onwards, all developing brain areas are sensitive to the effects of stress hormones; however, some areas undergo rapid growth during key critical windows. From birth to 2 years of age, the developing hippocampus is most vulnerable to the effects of stress. By contrast, exposure to stress from birth to late childhood leads to changes in amygdala volume, which continues to develop until the late 20s.

Fig. 1. The life cycle model of stress. Reproduced with permission of the Nature Publishing Group from Lupien et al. [ 6 ].
During adolescence, the hippocampus is fully organized, the amygdala continues to develop, and finally the frontal lobe undergoes important maturation. Consequently, stress exposure during this transition into adulthood can have major effects on the frontal cortex. Studies show that adolescents are highly vulnerable to stress because of pubertal changes in gonadic hormones and sensitivities of the hypothalamic-pituitary-adrenal axis that can persist into adulthood as potentiation/incubation effects. In adulthood and during aging, the brain regions that undergo the most rapid decline as a result of senescence are once again highly vulnerable to the effects of stress hormones. This leads to the manifestation of incubated effects from earlier life on the brain, known as manifestation effects or maintenance effects [ 6 ].
Lifelong brain changes ultimately diminish the organism’s ability to adapt, leading to subtle recalibrations in stress responsivity that could be used to detect disease trajectories [ 7 ]. According to the life cycle model of stress, regional volumes of these neurological structures in conjunction with biological signatures (e.g. hypercortisolism vs. hypocortisolism) can be used to predict differential risk profiles for specific psychopathologies (e.g. depression vs. PTSD) in adulthood as well as to inform when certain traumas might have occurred in early life [ 6 ]. While direct measurement of central nervous system substrates is costly and potentially invasive, indirect assessment using peripheral biomarkers routinely collected in blood draws can be used to infer AL levels. By interpreting this information in an alternative manner, the AL model proposes a temporal pathophysiological cascade useful for future early detection strategies for both physical and psychiatric morbidity.
Pathogenesis Temporal Cascade of Allostatic Load Mediators
Multiple mediators of adaptation are involved and interconnected in nonlinear networks [ 7 ]. When chronically stressed, the biphasic effects of numerous biomarkers eventually lead to AL and disease in a tripartite sequence: (1) overactivation of primary mediators such as stress hormones and pro-and anti-inflammatory cytokines induce primary effects on cellular activities; (2) subsequent secondary outcomes, whereby metabolic, cardiovascular, and second-order immune biomarkers become dysregulated, and (3) culmination in tertiary outcomes or clinical endpoints [ 7 ].
The AL model proposes that, by measuring the multisystemic, reciprocal interactions among primary mediators, primary effects, and secondary outcomes, individuals at a high risk for tertiary outcomes can be identified [ 8 ]. Physicians already routinely incorporate many related biomarkers in typical blood work, although attention is primarily placed on values reaching clinically significant levels. By including additional biomarkers, identifying preclinical values, and triangulating methods with interdisciplinary measures (e.g. genetic assessment, neuropsychological testing, clinical interviews, psychometrics, etc.), advances in diagnostic, treatment, and prevention strategies could be improved.
Allostatic Load Index
Epidemiological work by Seeman et al. [ 9 ] has led to AL algorithms predictive of numerous tertiary/clinical outcomes. Utilization of longitudinal data from the MacArthur studies on the Successful Aging cohort led to a count-based AL index representing the following 10 biomarkers: 12-hour urinary cortisol, epinephrine, and norepinephrine output; serum dehydroepiandrosterone-sulphate, high-density lipoprotein (HDL) and HDL-to-total cholesterol ratio; plasma glycosylated hemoglobin; aggregate systolic and diastolic blood pressures, and finally the waist-to-hip ratio. Individuals’ values falling within high-risk quartiles with respect to the sample’s biomarker distributions are dichotomized as ‘1’ and those within normal ranges as ‘0’. Once tabulated, these values are summed to yield an AL index ranging from a possible 0 to 10 which can then be used to predict health outcomes. Beyond these traditional biomarkers, many others have been incorporated into dozens of studies worldwide ( fig. 2 ) using similar count-based formulations and/or sophisticated statistical analyses.
Clinical Allostatic Load Index Formula
The AL index is thus far a research index with the promising possibility of becoming a clinical tool. It must therefore become accessible to medical professionals [ 10 ]. In this endeavor, the following shall demonstrate a simple formulation to calculate an AL index based on clinical reference ranges used routinely for diagnostic purposes. For each biomarker value included, a subclinical cutoff can be easily calculated based on normative clinical ranges.

Fig. 2. Frequencies of biomarkers repeatedly included in approximately 60 AL studies conducted between 1997 and 2010. TC = Total cholesterol; HDL = high-density lipoprotein; LDL = low-density lipoprotein.
Let us consider, as an example, total cholesterol levels with a normal range of 3.3-5.2 nmol/l. First, to determine the range, subtract the lower limit from the upper limit (5.2-3.3 = 1.9). Next, to determine the quartile, divide the range by four (1.9/4 = 0.475). Finally, to determine the cutoff, either subtract the quartile from the upper limit for the upper cutoff (5.2-0.475 = 4.725) or add the quartile to the lower limit for the lower cutoff (3.3 + 0.475 = 3.775) in the case of biomarkers like HDL cholesterol, DHEA-S, and albumin, whereby lower levels denote danger. Based on this example, a patient with total cholesterol at 4.725 nmol/l or higher would get a score of ‘1’ while values below this cutoff would be scored as ‘0’. A clinical AL index is therefore the sum of subclinically dysregulated biomarkers for each individual. Our previous work found that a clinical AL index was associated with increased subjective reports of chronic stress, frequency of burnout symptoms, and hypocortisolemic profiles characteristic of fatigue states [ 11 ]. While this formulation is designed for medical practice, it does not yield cutoffs that are exceedingly different from those based on biomarker distributions based on sample distributions generally used in empirical AL studies summarized in the following section.
Summary of Allostatic Load Research Findings
A recent review by Juster et al. [ 8 ] of nearly 60 empirical studies suggests that AL indices incorporating subclinical ranges for numerous biomarkers (mean = 10; range = 4-17) predict clinical outcomes better than traditional biomedical methods that address only clinical thresholds for single biomarkers. Importantly, AL inclusion of neuroendocrine and/or immune biomarkers is stronger than metabolic syndrome parameters or systemic clusters.
As summarized in table 1 , increased AL indices correspond either cross-sectionally or longitudinally to a plethora of antecedents (e.g. socioeconomic disadvantage, poor social networks, workplace stress, maladaptive personality traits, lifestyle behaviors, genetic polymorphisms, etc.) and consequences (e.g. mortality, cardiovascular disease, psychiatric symptoms, cognitive decline, physical/mobility limitations, neurological atrophy, etc.). Individual differences in unique configurations of these antecedents should be explored further, as they are experienced differently by each sex throughout life and are strong mediators and/or moderators of AL consequences.
Age and Sex Diff

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