Ambiguous Genitalia and Intersexuality 

  • Author: Joel Hutcheson, MD; Chief Editor: Marc Cendron, MD   more...
 
Updated: Jan 11, 2012
 

Background

Disorders of sexual development (DSD), formerly termed intersex conditions, are among the most fascinating conditions encountered by the clinician. The ability to diagnose these conditions has advanced rapidly in recent years. In most cases today, clinicians can promptly make an accurate diagnosis and counsel parents on therapeutic options. However, the paradigm of early gender assignment has been challenged by the results of clinical and basic science research, which show that gender identity development likely begins in utero. While the techniques of surgical genital reconstruction have been mastered, the understanding of the psychological and social implications of gender assignment has shifted the paradigm away from early reconstruction in some cases. This article focuses on newborn evaluation and the differential diagnoses in children with DSD, including children with ambiguous genitalia.[1, 2]

Classification of disorders of sexual development

Recently, the Lawson Wilkins Pediatric Endocrine Society (LWPES) and the European Society for Paediatric Endocrinology (ESPE) have published proposed changes to the nomenclature and definitions of disorders in which the development of chromosomal, gonadal, or phenotypic sex is atypical. The rationale behind these proposals was to change the nomenclature to reflect advances in our understanding of the pathophysiology of these disorders while being sensitive to the needs and concerns of patients affected by them. Below are listed previous terminology and the revised nomenclature.

Table. Previous Terminology and Revised Nomenclature of Disorders of Sexual Development (Open Table in a new window)

Previous Revised
Female pseudohermaphrodite46,XX DSD
Male pseudohermaphrodite46,XY DSD
True hermaphroditeOvotesticular DSD
XX male46,XX testicular DSD
XY sex reversal46,XY complete gonadal dysgenesis

This terminology mainly reflects the chromosomal sex or the gonadal tissue associated with the disorder.

The following are examples of DSD classifications based on the new nomenclature:

  • Sex chromosome DSD
  • 46,XY DSD
    • Disorders of testicular development (complete and partial gonadal dysgenesis)
    • Disorders of androgen synthesis (complete and partial androgen insensitivity, disorders of antimüllerian hormone [AMH]/receptor, androgen biosynthesis defect)
    • Other (severe hypospadias, cloacal exstrophy)
  • 46,XX DSD
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Pathophysiology

Adequate comprehension of normal and abnormal sexual differentiation is essential to understanding DSD. A summary of current knowledge regarding the embryology and classification of these conditions provides an appropriate introduction to the topic.

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Embryology of Sexual Differentiation

Overview

Phenotypic sex determination begins with genetic sex and follows a logical cascade: chromosomal sex determines gonadal sex, which determines phenotypic sex. The type of gonad present determines the differentiation/regression of the internal ducts (ie, müllerian and wolffian ducts) and ultimately determines the phenotypic sex. Gender identity is determined not only by the phenotypic appearance of the individual but also by the brain's prenatal and postnatal development as influenced by the environment.

Gonadal differentiation

During the second month of fetal life, the indifferent gonad is guided to develop into a testis by genetic information present on the short arm of the Y chromosome. Testis-determining factor (TDF) is a 35–kilobase pair (kbp) sequence on the 11.3 subband of the Y chromosome, an area termed the sex-determining region of the Y chromosome (SRY). When this region is absent or altered, the indifferent gonad develops into an ovary.

The existence of patients with 46,XX testicular DSD, who have testicular tissue in the absence of an obvious Y chromosome or SRY genetic material, clearly requires other genetic explanations. Other genes important to testicular development include DAX1 on the X chromosome, SF1 on band 9q33, WT1 on band 11p13, SOX9 on bands 17q24-q25, and AMH on band 19q13.3. Fetal ovaries develop when the TDF gene (or genes) is absent.

Differentiation of internal ducts

Development of the internal ducts results from a paracrine effect from the ipsilateral gonad. Jost's classic research with rabbits greatly clarified the gonad's role in controlling subsequent development of internal sex ducts and external genital phenotype.[3]

When testicular tissue is absent, the fetus morphologically begins and completes the internal sex duct development and external phenotypic development of a female. When testicular tissue is present, two produced substances appear to be critical for development of male internal sex ducts and an external male phenotype, namely, testosterone and müllerian-inhibiting substance (MIS) or AMH.

Testosterone is produced by testicular Leydig cells and induces the primordial wolffian (mesonephric) duct to develop into the epididymis, vas deferens, and seminal vesicle. A spatial relationship is important in the effect of testosterone. Wolffian structures located closest to the source of testosterone undergo the greatest degree of male differentiation. Thus, patients with ovotesticular DSD often have a degree of wolffian development near testicular tissue, even when joined with an ovary as an ovotestis. No wolffian development is expected in association with a streak gonad or a non–testosterone-producing dysgenetic testis.

High local testosterone levels (paracrine effect) appear to be necessary for wolffian duct differentiation because maternal ingestion of androgens does not cause male internal differentiation in a female fetus, nor does this differentiation occur in females with CAH, also termed adrenogenital syndrome.

MIS is produced by the Sertoli cells of the testis and is critical to normal male internal duct development. MIS is a protein with a molecular weight of 15,000 d that is secreted by the testis beginning in the eighth fetal week. The prime role of MIS is to repress passive development of the müllerian ducts (eg, fallopian tubes, uterus, upper vagina). In a male fetus with normal testicular function, MIS represses müllerian duct development, while testosterone stimulates wolffian duct development.

The influences of testosterone and estrogen apparently modulate but do not isolate the role of MIS. Local testosterone production appears to enhance the inhibition of müllerian duct development produced by MIS, while estrogens may interfere with MIS action, resulting in a degree of müllerian duct development. This suggests that müllerian development may be more complex than initially appreciated, and the research helps explain the variable internal sex duct anatomy that occurs in some of the more complex intersex states.

Differentiation of external genitalia

The external genitalia of both sexes are identical during the first 7 weeks of gestation. Without the hormonal action of the androgens testosterone and dihydrotestosterone (DHT), external genitalia appear phenotypically female. In the gonadal male, differentiation toward the male phenotype actively occurs over the next 8 weeks. This differentiation is moderated by testosterone, which is converted to 5-DHT by the action of an enzyme, 5-alpha reductase, present within the cytoplasm of cells of the external genitalia and the urogenital sinus. DHT is bound to cytosol androgen receptors within the cytoplasm and is subsequently transported to the nucleus, where it leads to translation and transcription of genetic material.

In turn, these actions lead to normal male external genital development from primordial parts, forming the scrotum from the genital swellings, forming the shaft of the penis from the folds, and forming the glans penis from the tubercle. The prostate develops from the urogenital sinus.

Incomplete masculinization occurs when testosterone fails to convert to DHT or when DHT fails to act within the cytoplasm or nucleus of the cells of the external genitalia and urogenital sinus. The timing of this testosterone-related developmental change begins at approximately 6 weeks of gestation with a testosterone rise in response to a surge of luteinizing hormone (LH). Testosterone levels remain elevated until the 14th week. Most phenotypic differentiation occurs during this period. After the 14th week, fetal testosterone levels settle at a lower level and are maintained more by maternal stimulation through human chorionic gonadotropin (hCG) than by LH. Testosterone's continued action during the latter phases of gestation is responsible for continued growth of the phallus, which is directly responsive to testosterone and to DHT.

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Epidemiology

Frequency

United States

DSD vary in frequency depending on their etiology. CAH is the most common cause of ambiguous genitalia in the newborn. Mixed gonadal dysgenesis (MGD) is the second most common cause of DSD. Hypospadias occurs at a rate of 1 case per 300 live male births; in fewer than 1% of patients, hypospadias occurs in combination with undescended testes. A large series at Children's Hospital in Boston found DSD in 50% of children with hypospadias and unilateral or bilateral cryptorchidism in which the gonads were impalpable.[4] Clinicians should suspect the possibility of a DSD in patients with both hypospadias and cryptorchidism.

International

Analysis of worldwide infant screening of 6.5 million newborns found the incidence of CAH to be 1 case per 15,000 live births. Frequency was highest in neonates of European Jewish, Hispanic, Slavic, or Italian descent.

Mortality/Morbidity

  • Medical aspects: Infants born with ambiguous genitalia represent a true medical and social emergency. Salt-wasting nephropathy occurs in 75% of infants born with CAH, the most common cause of ambiguous genitalia. If unrecognized, the resulting hypotension can cause vascular collapse and death. Male infants with this syndrome may be phenotypically normal, and the diagnosis may be missed.
  • Psychosocial aspects: Modern treatment of infants with ambiguous genitalia involves a team-oriented approach. This gender-assignment team usually involves neonatologists, geneticists, endocrinologists, surgeons, counselors, and ethicists. The goal is to provide appropriate medical support and counseling regarding care and therapy. The topic of early gender reassignment is currently under debate.

Sex

DSD may result in individuals who do not conform to traditional male or female classifications.

Age

DSD typically are diagnosed at birth in infants with ambiguous genitalia. Disorders associated with phenotypic males and females may be diagnosed much later. The classic presentation of MIS deficiency is a boy with a hernia on one side and an impalpable contralateral gonad. At the time of surgery, a uterus and fallopian tubes are noted along with normal wolffian structures. Diagnosis in 46,XY phenotypic females with complete androgen insensitivity usually occurs after puberty during an evaluation for primary amenorrhea.

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Contributor Information and Disclosures
Author

Joel Hutcheson, MD  Consulting Staff, Departments of Surgery and Urology, Pediatric Surgical Associates

Joel Hutcheson, MD is a member of the following medical societies: American Academy of Pediatrics and American Urological Association

Disclosure: Nothing to disclose.

Coauthor(s)

Howard M Snyder III, MD  Professor, Department of Surgery, Division of Pediatric Urology, University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia

Howard M Snyder III, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Surgeons, American Medical Association, American Urological Association, and National Kidney Foundation

Disclosure: Nothing to disclose.

Specialty Editor Board

Martin David Bomalaski, MD, FAAP  Pediatric Urologist, Alpine Urology

Martin David Bomalaski, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, and American Urological Association

Disclosure: Nothing to disclose.

Mary L Windle, PharmD  Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Harry P Koo, MD  Chairman of Urology Division and Director of Pediatric Urology, Professor of Surgery, Virginia Commonwealth University School of Medicine, Medical College of Virginia; Director of Urology, Children's Hospital of Richmond

Harry P Koo, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Surgeons, and American Urological Association

Disclosure: Nothing to disclose.

Paul D Petry, DO, FACOP, FAAP  Consulting Staff, Freeman Pediatric Care, Freeman Health System

Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association

Disclosure: Nothing to disclose.

Chief Editor

Marc Cendron, MD  Associate Professor of Surgery, Harvard School of Medicine; Consulting Staff, Department of Urological Surgery, Children's Hospital Boston

Marc Cendron, MD is a member of the following medical societies: American Academy of Pediatrics, American Urological Association, European Society for Paediatric Urology, Johns Hopkins Medical and Surgical Association, New Hampshire Medical Society, Society for Fetal Urology, and Society for Pediatric Urology

Disclosure: Nothing to disclose.

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Patient with 46,XY disorder of sexual development. Note the masculinized appearance of the genitalia with an enlarged phallus and scrotal appearance of the labia.
Table. Previous Terminology and Revised Nomenclature of Disorders of Sexual Development
Previous Revised
Female pseudohermaphrodite46,XX DSD
Male pseudohermaphrodite46,XY DSD
True hermaphroditeOvotesticular DSD
XX male46,XX testicular DSD
XY sex reversal46,XY complete gonadal dysgenesis
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