Hermaphroditism

Dr. Arvind Kumar

Introduction

Hermaphroditism refers to a group of congenital conditions in which an individual shows discordance between chromosomal sex, gonadal sex, and phenotypic (external genital) sex.

In simple words:

Sex development does not follow the normal male or female pathway.

In modern medical terminology, hermaphroditism is included under:

Disorders of Sex Development (DSD)

Normal Sex Determination

Before understanding hermaphroditism, it is important to know normal sex development.

Sex development occurs at three levels:

  • Chromosomal sex

    • Established at fertilization

    • XX → genetic female

    • XY → genetic male

  • Gonadal sex

    • SRY gene on Y chromosome induces testis formation

    • Absence of SRY → ovary formation

  • Phenotypic sex

    • Depends on hormonal influence

    • Testosterone & dihydrotestosterone (DHT) → male genitalia

    • Absence of androgens → female genitalia

What Goes Wrong in Hermaphroditism?

Hermaphroditism occurs when:

  • Chromosomes, gonads, and external genitalia do not match

  • Hormonal production or response is abnormal

  • Genetic mutations affect sexual differentiation

 

Classification of Hermaphroditism

Hermaphroditism is broadly classified into:

I. True Hermaphroditism

(Ovotesticular Disorder of Sex Development)

A condition in which an individual possesses both ovarian and testicular tissue, either as separate gonads or combined in a single gonad known as an ovotestis.

Features

  • Chromosomal pattern: Most commonly 46, XX; rarely 46, XY or mosaic (XX/XY)
  • Gonads: Ovary and testis (separate) or ovotestis
  • External genitalia: Usually ambiguous, may lean toward male or female
  • Diagnosis: Confirmed by histopathological examination of gonadal tissue

Clinical Importance

  • Extremely rare
  • Fertility is uncommon
  • Requires careful clinical, hormonal, and genetic evaluation

II. Pseudohermaphroditism

In pseudohermaphroditism, the gonads are of one sex, but the external genitalia resemble those of the opposite sex.

II-A. Male Pseudohermaphroditism

(46, XY Disorder of Sex Development)

An individual with male chromosomal sex (XY) and testes, but with female or ambiguous external genitalia due to inadequate androgen action.

Characteristics

  • Chromosomes: 46, XY
  • Gonads: Testes (often undescended)
  • Internal genitalia: No uterus or fallopian tubes
  • External genitalia: Female-like or ambiguous

Common Causes

  • Androgen insensitivity syndrome
  • Defects in testosterone synthesis
  • Androgen receptor abnormalities

II-B. Female Pseudohermaphroditism

(46, XX Disorder of Sex Development)

An individual with female chromosomal sex (XX) and ovaries, but with masculinized external genitalia, usually due to excess androgen exposure.

Characteristics

  • Chromosomes: 46, XX
  • Gonads: Ovaries present
  • Internal genitalia: Uterus and fallopian tubes present
  • External genitalia: Masculinized (e.g., clitoromegaly, labial fusion)

Most Common Cause

  • Congenital adrenal hyperplasia (CAH)

III. Gonadal Dysgenesis

A group of conditions characterized by defective or absent gonadal development, leading to inadequate sex hormone production.

Features

  • Gonads: Streak gonads or dysgenetic gonads
  • Chromosomes: May be XX, XY, or mosaic
  • External genitalia: Often ambiguous or female-like

Types

  • Pure gonadal dysgenesis
  • Mixed gonadal dysgenesis

Table

Category Chromosomal Sex Gonads External Genitalia
True Hermaphroditism XX / XY / Mosaic Ovary + Testis Ambiguous
Male Pseudohermaphroditism XY Testes Female-like
Female Pseudohermaphroditism XX Ovaries Male-like
Gonadal Dysgenesis Variable Streak gonads Ambiguous/Female

 

Etiopathogenesis

The etiopathogenesis of hermaphroditism involves disturbances at one or more critical stages of sexual differentiation, namely chromosomal sex, gonadal differentiation, hormonal synthesis/action, and phenotypic development. These abnormalities may arise due to genetic, enzymatic, hormonal, or environmental factors acting during fetal life.

1. Abnormalities in Chromosomal Sex Determination

Chromosomal sex is fixed at fertilization (XX or XY). Errors at this level lead to discordant downstream development.

Mechanisms

  • Sex chromosome aneuploidy
  • Mosaicism or chimerism

Examples

  • 46,XX/46,XY mosaicism → may lead to ovotesticular DSD
  • Structural abnormalities of X or Y chromosome

Pathogenic Impact

  • Inconsistent signaling for gonadal differentiation
  • Simultaneous or incomplete development of male and female gonads

2. Defects in Gonadal Differentiation

Normal gonadal development depends on tightly regulated gene expression.

Genes Involved

  • SRY (Sex-determining Region of Y chromosome)
  • SOX9
  • WT1
  • SF-1 (NR5A1)
  • DAX1

Pathogenic Mechanisms

  • Failure of SRY expression → testis does not develop in XY individuals
  • Partial gene activation → mixed gonadal tissue (ovotestis)

Outcome

  • True hermaphroditism (ovotesticular DSD)
  • Dysgenetic testes or streak gonads

3. Disorders of Steroid Hormone Biosynthesis

Steroid hormones play a central role in phenotypic sex development.

Enzymatic Defects

  • 21-hydroxylase deficiency
  • 11β-hydroxylase deficiency
  • 17α-hydroxylase deficiency

Biochemical Consequences

  • ↓ Cortisol synthesis
  • ↑ ACTH → adrenal hyperplasia
  • ↑ Androgen excess or deficiency

Clinical Result

  • 46,XX individuals → virilization (female pseudohermaphroditism)
  • 46,XY individuals → undervirilization

4. Defective Androgen Action

Even with normal hormone synthesis, tissues may fail to respond.

Mechanisms

  • Androgen receptor mutation
  • Impaired DHT formation

Conditions

  • Androgen insensitivity syndrome (AIS)
  • 5α-reductase deficiency

Pathogenesis

  • Testosterone present but ineffective
  • Failure of male external genital development

Outcome

  • Male pseudohermaphroditism
  • Female-like external genitalia in genetic males

5. Abnormal Anti-Müllerian Hormone (AMH) Function

AMH causes regression of Müllerian ducts in males.

Pathogenic Causes

  • AMH deficiency
  • AMH receptor defects

Effect

  • Persistence of uterus and fallopian tubes in XY individuals

6. Errors in Embryological Timing

Sexual differentiation is time-sensitive.

Critical Period

  • 6–12 weeks of gestation

Disruption Leads To

  • Partial virilization
  • Ambiguous genitalia

Delayed or insufficient hormonal exposure during this window leads to incomplete sex differentiation.

7. Maternal and Environmental Factors

Exogenous Androgen Exposure

  • Maternal androgen-secreting tumors
  • Intake of androgenic drugs during pregnancy

Endocrine Disruptors

  • Pesticides
  • Industrial chemicals with estrogenic/anti-androgenic effects

Outcome

  • Virilization of female fetus
  • Feminization of male fetus

8. Epigenetic and Regulatory Mechanisms

Recent studies highlight the role of:

  • DNA methylation abnormalities
  • Histone modification defects
  • Altered transcription factor binding

These mechanisms modify gene expression without changing DNA sequence, contributing to phenotypic variability.

 

Clinical Presentation

1. At Birth

  • Ambiguous genitalia
  • Micropenis / enlarged clitoris
  • Hypospadias, bifid scrotum
  • Discordance between external genitalia and palpable gonads

2. Infancy & Childhood

  • Inguinal hernia with gonads in phenotypic females
  • Abnormal genital growth
  • Salt-wasting crisis in CAH (vomiting, dehydration, shock)

3. At Puberty

  • Delayed or absent puberty
  • Virilization in females
  • Gynecomastia in males
  • Primary amenorrhea

4. Adolescence & Adulthood

  • Infertility
  • Sexual dysfunction
  • Menstrual abnormalities

5. Associated Features

  • Undescended or abnormal gonads
  • Atypical secondary sexual characteristics
  • Psychological distress / gender identity issues

 

Diagnostic Evaluation of Hermaphroditism

1. Initial Clinical Assessment

A. Detailed History

  • Antenatal history
    • Maternal drug intake (androgens, progestins)
    • Virilization of mother during pregnancy
  • Family history
    • Similar conditions
    • Consanguinity
    • Neonatal deaths (suggesting CAH)
  • Developmental history
    • Pubertal timing
    • Menstrual history
    • Fertility issues

B. Physical Examination

  • External genitalia:
    • Phallic size
    • Urethral opening position
    • Labioscrotal fusion
  • Palpation for gonads (inguinal / labioscrotal)
  • Degree of virilization (Prader staging in 46,XX)
  • Secondary sexual characteristics (Tanner staging)

Do not assign sex clinically without investigations.

2. Genetic Evaluation

A. Karyotyping (First-Line Test)

  • Determines chromosomal sex:
    • 46,XX
    • 46,XY
    • Mosaic (46,XX/46,XY)
  • Helps classify DSD category

B. Advanced Genetic Tests

  • FISH (SRY gene detection)
  • Microarray analysis
  • Targeted gene sequencing (SRY, SOX9, WT1, NR5A1)

Essential in suspected true hermaphroditism and gonadal dysgenesis.

3. Hormonal (Endocrine) Evaluation

Baseline Hormone Assays

  • Testosterone
  • Dihydrotestosterone (DHT)
  • Estradiol
  • LH and FSH
  • Anti-Müllerian Hormone (AMH)
  • 17-hydroxyprogesterone (screening for CAH)
  • Cortisol and ACTH

Interpretation

  • ↑ 17-OHP → congenital adrenal hyperplasia
  • Normal testosterone + female phenotype → androgen insensitivity
  • Low testosterone in XY → biosynthetic defect

Dynamic Hormonal Tests

  • hCG stimulation test
    • Assesses Leydig cell function
  • ACTH stimulation test
    • Confirms adrenal enzyme deficiencies

4. Biochemical Investigations

  • Serum electrolytes (Na⁺, K⁺) – CAH salt-wasting
  • Blood glucose – hypoglycemia risk
  • Renin and aldosterone levels

Life-saving in neonates suspected of CAH.

5. Imaging Studies

A. Ultrasonography

  • Detection of:
    • Uterus
    • Ovaries
    • Undescended testes

B. MRI Pelvis/Abdomen

  • Better delineation of internal genital organs
  • Gonadal localization
  • Mullerian or Wolffian structures

6. Endoscopic and Radiological Procedures

  • Genitography:
    • Defines urogenital sinus
    • Vaginal and urethral anatomy
  • Cystoscopy (selected cases)

7. Histopathological Examination

Gonadal Biopsy (Gold Standard)

  • Confirms:
    • Ovary
    • Testis
    • Ovotestis
  • Detects premalignant changes

Mandatory before definitive diagnosis of true hermaphroditism.

8. Psychological and Psychiatric Assessment

  • Gender identity development
  • Emotional well-being
  • Family counseling
  • Long-term psychosocial planning

Psychological evaluation is as important as biological diagnosis.

9. Multidisciplinary Team Approach

Includes:

  • Endocrinologist
  • Pediatric surgeon / Urologist
  • Geneticist
  • Pathologist
  • Psychiatrist / Psychologist
  • Ethics committee