Principles of Gender-Specific Medicine

Gender in the Genomic Era

Marianne Legato J, Marianne J. Legato

• Publisher: Academic Press
• Year: 2017
• Edition: 3
• eBook ISBN:
  9780128035429
• Topic: Medicine
• Subtopic: Endocrinology & Metabolism

The announcement that we had decoded the human genome in 2000 ushered in a new and unique era in biomedical research and clinical medicine. This Third Edition of Principles of Gender-Specific Medicine focuses, as in the past two editions, on the essentials of sexual dimorphism in human physiology and pathophysiology, but emphasizes the latest information about molecular biology and genomic science in a variety of disciplines. Thus, this edition is a departure from the previous two; the editor solicited individual manuscripts from innovative scientists in a variety of fields rather than the traditional arrangement of sections devoted to the various subspecialties of medicine edited by section chiefs. Wherever it was available, these authors incorporated the latest information about the impact of the genome and the elements that modify its expression on human physiology and illness. All chapters progress translationally from basic science to the clinical applications of gender-specific therapy and suggest the most important topics for future investigation. This book is essential reading for all biomedical investigators and medical educators involved in gender-specific medicine. It will also be useful for primary care practitioners who need information about the importance of sex and gender in the prevention, diagnosis and treatment of illness. Winner of the 2018 PROSE Award in Clinical Medicine from the Association of American Publishers! - 2018 PROSE Awards - Winner, Award for Clinical Medicine: Association of American Publishers - Outlines sex-specific differences in normal human function and explains the impact of age, hormones, and environment on the incidence and outcome of illness - Reflects the latest information about the molecular basis of the sexual dimorphism in human physiology and the experience of disease - Reviews the implications of our ever-improving ability to describe the genetic basis of vulnerability to disease and our capacity to alter the genome itself - Illustrates the importance of new NIH guidelines that urge the inclusion of sex as a variable in research protocols

Chapter 1

Normal and Variant Sex Development

Olaf Hiort, University of Lübeck, Lübeck, Germany

Abstract

Sex development is the biological pathway for any species to allow reproduction and therefore survival over generations. This has led to highly complex arrangements during evolution to allow offspring to differentiate into either male or female. Interestingly, many of the morphologic patterns arise from common denominators and their genetic pathways have been elucidated. Furthermore, the phenotype of any individual's being male or female is largely dependent on endocrine influences from the developing gonad. Many of the pathways have been described as being altered leading to a variant sex development, which is referred to in the medical terminology as Differences or Disorders of Sex Development (DSD). People with DSD have taught us a lot not only about the biological basis of sex development, but also about the medical management and social acceptance of such conditions. Recent discussions both in the professional fields and among societal stakeholders have led to a rethinking of personal rights, social participation, and concepts of gender in general.

Keywords

Sex development; genetics; endocrinology; embryology; Disorders of Sex Development

Outline

1.1 Physiology of Biological Sex Development 1

1.1.1 Background 1

1.1.2 Chromosomal Sex 2

1.1.3 Gonadal Sex 2

1.1.4 Development of Internal Genital Structures 3

1.1.5 Development of External Genital Structures 3

1.1.6 Extragenital Sexual Dimorphism and Brain Sex 3

1.2 Pathophysiology 3

1.2.1 Disorders or Differences of Sex Development—Nomenclature and Classification 3

1.2.2 Sex Chromosome Abnormalities—Turner Syndrome and Klinefelter Syndrome 5

1.2.3 Abnormalities of Gonadal Development 5

1.2.4 Disorders of Hormone Synthesis and Actions 6

1.2.5 Unclassified Conditions 8

1.3 Diagnostic Procedures 8

1.3.1 Clinical Approach 8

1.3.2 Genetic and Laboratory Analysis 9

1.3.3 Imaging 9

1.4 Management of DSD 10

1.4.1 Centers of Competence and the Interdisciplinary Team Approach 10

1.4.2 Sex Assignment 11

1.5 Therapy 11

1.5.1 Endocrine Therapy 11

1.5.2 Surgical Therapy 12

1.6 Conclusion and Outlook 13

References 14

1.1 Physiology of Biological Sex Development

1.1.1 Background

The biological sex of the human being will be defined by the genetic determination of the differentiation of the gonads to develop either into a testis or an ovary. The genetic pathway usually starts with the initial setting of either a 46,XX or a 46,XY karyotype. Subsequently, a tightly regulated cascade of both sex chromosome and autosome derived genetic expression pathways is initiated. From the bipotent gonadal anlagen then ovarian or testicular cells develop, which in due course set the stage for hormone synthesis, which in turn allows the shaping of the individual phenotype into either male or female. These processes occur in a precise stepwise and time-dependent manner and any disruption at sensitive time intervals will allow deviation from the usual pathways.

These conditions are described as Disorders or Differences of Sex Development (DSD).¹ DSD encompasses mostly rare to very rare genetically determined variants of a discrepancy between chromosomal, gonadal, and phenotypic sex. It is unclear at this time if also external associated, nongenetic factors may disrupt the endocrine pathways and thus lead to DSD. Sex development is not only related to development of genital structures, but also includes sexually-dimorphic development of brain structures. Therefore, DSD will affect not only the appearance of primary genital structures and subsequent sexual maturation at puberty, but also gender identity. Furthermore, especially the initial genetic steps of gonadal development may also be involved in the differentiation and function of other organs, such as the adrenal, the skeletal system, or even the neurological system. Therefore, patients with DSD conditions may have associated endocrine illnesses and other system disorders, requiring expert medical attention.

1.1.2 Chromosomal Sex

The chromosomal sex of an individual is determined with the fusion of egg and sperm at the time of conception. Usually, one X chromosome is inherited from the mother, while the sperm from the father may provide either an X or a Y chromosome to account for the 46,XX or 46,XY karyotype of the embryo. This genetic layout is seen as a starting point of sex development in the principally “unsexed” child. The chromosomes themselves may harbor sex-specific and sex-unspecific, pseudo-autosomal genes. Sex chromosome division may be altered either prior to conception or during the first cell divisions of the blastocyst, leading to numerical aberrations. Sex chromosome trisomies as 47,XXY or monosomies as 45,X are well recognized, but also higher numbers of sex chromosomes have been described in humans. Mosaicism like 45,X/46,XY are the result of the loss of a sex chromosome during the first cell cycles. Also chimeric alterations like 46,XX/46,XY may occur. It is believed that the presence of Y-chromosomal material in any individual may lead at least to partial testicular development of the gonadal structures and, hence, may also lead to differences in phenotypic development of that individual.

1.1.3 Gonadal Sex

For more than 25 years it has been known that testicular determination from the bipotent gonadal anlagen is initiated with the expression of the SRY-gene from the Y-chromosome.² SRY stands for “Sex Determining Region of the Y-Chromosome.” Subsequently, the consecutive genetic cascade has been elucidated, where SRY in turn leads to upregulation of SOX9 (SRY-related HMG-box gene 9) in the pre-Sertoli cells of the developing testes.³ The physiologic role of SRY and SOX9 has been shown in elaborate animal studies, which demonstrated that in the absence of SRY, mice were able to develop ovaries despite a typical male karyotype, while mice with a typical female karyotype were able to develop testes if SOX9 was overexpressed. In humans, duplication of SOX9 in 46,XX individuals is associated with the development of testes, while deleterious mutations in SOX9 lead to a failure of gonadal development in 46,XY individuals and also produces associated bone malformations called campomelic dysplasia. Following expression of SRY and SOX9, a battery of other genes is expressed with specific functions (for review see Ref. 4). One example is DHH, called Desert Hedge Hog, which is expressed in the Sertoli cells, secreted, and acts as an initiator of the differentiation of the Leydig cells.⁵

Other examples include NR5A1, which codes for a protein called SF-1 (Steroidogenic Factor 1), involved both in testicular differentiation as well as the initiation of steroidogenesis in the Leydig cells.⁶ It also regulates the secretion of Anti-Mullerian Hormone from the Leydig cells and positively regulates SOX9. GATA4 in turn regulates not only several of the genes involved in steroidogenesis, but is also involved in the development of the heart^7–9; therefore patients have been identified with DSD and severe heart defects like atrioventricular septal defects.

If testicular development is not initiated because of SRY not being expressed in the 46,XX karyotype, ovarian development begins at about the 10th week of gestation. WNT4 (Wingless type MMTV integration side family, member 4) will foster ovarian determination by suppressing Leydig cells. Homozygous mutations in WNT4 may lead to testicular development in genetically female mice, while in contrast humans with 46,XY karyotype and gene duplication of WNT4 develop 46,XY DSD.¹⁰ Several further genes have been described that actively pursue ovarian development in an expression level-related and therefore dose-dependent manner.

A major focus of ongoing research is identifying more genes whose expression is directly involved in gonadal development and to elucidate the interplay between these factors in sex development. It seems that in developmental biology, the sex determining genes are involved in a “battle of the sexes,” in which the sex-specific factors defend their own sex-developing program, while they downregulate the contra-sex side. At this time, testicular development is seen as the more determined part, with ovarian development being more labile¹¹ due to the leading role of SRY in gonadal determination and the decisive activity of androgens.

1.1.3.1 Sex Differentiation and Somatic Sex

Sex differentiation refers to the development of the phenotypic features of sex, namely the development of the internal and external male or female structures. This is mostly a hormone driven process, and depends on the presence or absence of either the Anti-Mullerian Hormone or androgenic sex steroids. This finally results in the male or female somatic sex.¹²

While female somatic sex does not depend on endocrine activity, male sex differentiation has to be seen as the active, hormone-dependent, and irreversible modification of the primarily bipotent tissue structures of the internal and external genital anlagen.¹³ Androgenic steroids such as testosterone will lead to irreversible downstream expression patterns of genes corresponding to induction of the male phenotype in cells of the genital tubercle.¹⁴ Thus, these androgenic steroids program th...

Table of contents

• Principles of Gender-Specific Medicine
• Chapter 1 Normal and Variant Sex Development
• Chapter 2 Gender Diagnoses
• Chapter 3 Gender Identity in Disorders of Sex Development
• Chapter 4 Female Sexual Function
• Chapter 5 Fertility Treatment and Preservation in Transgender Men and Women
• Chapter 6 Standards of Care for the Health of Transsexual, Transgender, and Gender-Nonconforming People
• Chapter 7 Sex-Dependent and -Independent Mechanisms in External Genitalia Development
• Chapter 8 The Transsexual Adult
• Chapter 9 Sexual and Gender Minority Individuals in Health Care
• Chapter 10 Sex Influences Exist at All Levels of Human Brain Function
• Chapter 11 Sex Differences in the Brain
• Chapter 12 Sexual Dimorphisms in the Nervous System of the Nematode Caenorhabditis elegans
• Chapter 13 Oxytocin and Brain Plasticity
• Chapter 14 Emotion and Gender-Specific Neural Processing in Men and Women
• Chapter 15 Behind the Mask
• Chapter 16 The Significance of Gender in Perinatal Medicine
• Chapter 17 Intrauterine Development of Sex Differences—Fetal Programming
• Chapter 18 Battle of the Sexes
• Chapter 19 All Cells Have a Sex
• Chapter 20 Sex-Specific Implications of Exposure to An Adverse Intrauterine Environment
• Chapter 21 Immune Response—The Impact of Biological Sex and Gender
• Chapter 22 Geoepidemiology and the Impact of Sex on Autoimmune Diseases
• Chapter 23 Gender and Gene Regulation in Human Immunity
• Chapter 24 Sex and Gender Specific Aspects—From Cells to Cardiovascular Disease
• Chapter 25 Estrogen
• Chapter 26 The Sexually Dimorphic Characteristics of the Pathophysiology and Treatment of Atrial Fibrillation
• Chapter 27 Gender Differences in Chronic Obstructive Pulmonary Disease—Current Knowledge and Deficits
• Chapter 28 Cancer
• Chapter 29 An Updated Overview of the Gender-Specific Response to Infection
• Chapter 30 Gender-Based Differences in Mortality in Indian Children Aged 5 to 14 years
• Chapter 31 Consideration of Biological Sex in Translating Regenerative Stem Cell Therapies
• Chapter 32 Adipose-Derived Stem Cells in Regenerative Medicine
• Chapter 33 Sex, Gender, and Pain
• Chapter 34 Sex and Gender Differences in Trauma Victims Presenting for Treatment
• Chapter 35 Women Do Worse Than Men—Gender-Specific Differences in Burn Patients
• Chapter 36 Exercise Physiology in Men and Women
• Chapter 37 Musculoskeletal Complaints in Male and Female Instrumental Musicians
• Chapter 38 Nutritional Genomics and Biological Sex
• Chapter 39 Microbiome
• Chapter 40 Sex and Gender Differences in Sleep Disorders
• Chapter 41 Gender Differences in Bladder and Kidney Cancers
• Chapter 42 The Complex Challenge of Blood Pressure Regulation
• Chapter 43 Gender at the Interface of Renal Aging
• Chapter 44 Gender Differences in Mobility of Elderly
• Chapter 45 Personalized Medicine in Space Flight, Part I
• Chapter 46 Personalized Medicine in Space Flight, Part II
• Chapter 47 Robots and Gender
• Chapter 48 Cyborgs
• Chapter 49 Precision Medicine and Challenges in Research and Clinical Implementation
• Chapter 50 Gender-Specific Medicine in Pharmaceutical Drug Discovery and Development
• Index