Hermaphroditism and Pseudohermaphroditism

Slide 1 · Hermaphroditism and

Pseudohermaphroditism

Developmental mechanisms, pathology, and current DSD classification

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish chromosomal, gonadal, ductal and external genital development.

Translate historical labels into current DSD terminology without conflating categories.

Explain androgen synthesis/action and gonadal differentiation disorders.

Apply a safe, systematic diagnostic and pathology-oriented approach.

Slide 3 · Scope: Textbook definition and clinical expansion

Robbins supplies the four-level model and historical distinctions in a short passage.

The following developmental mechanisms and disease examples are expanded from specialist references.

Contemporary DSD terms are used for clinical interpretation; Historic names appear only for comparison.

Not every DSD presents with atypical genitalia.

Slide 4 · Four levels of sex-related development

Chromosomal

Sex chromosome constitution, including mosaicism and gene-level exceptions

Gonadal

Ovarian, testicular, dysgenetic or combined gonadal tissue

Ductal

Müllerian and Wolffian derivative development

External anatomy

Genital morphology shaped by local endocrine signals

Slide 5 · Chromosomal constitution is one level—not a diagnosis

46,XX and 46,XY are common chromosomal complements.

Mosaicism and structural rearrangements can produce discordant tissue lineages.

SRY translocation or loss of function can uncouple a simple X/Y prediction from gonadal differentiation.

Chromosome analysis is necessary in many evaluations but not sufficient alone.

Slide 6 · From gonadal primordium to tissue phenotype

Embryonic gonadal tissue starts in a bipotential state.

Gene regulatory programs promote testicular or ovarian pathways.

Mosaic or altered signaling can yield dysgenetic or mixed tissue.

Bipotential gonad

Sex-determining gene networks

Differentiated or dysgenetic gonad

Slide 7 · Gonadal sex is defined histologically

Testicular tissue is identified by seminiferous tubules and supporting cell lineages.

Ovarian tissue is characterized by ovarian stroma and follicles when present.

A streak gonad is dysgenetic tissue, not equivalent to a functioning ovary or testis.

Gonadal histology can differ between sides and within a single gonad.

Slide 8 · Ductal sex: Two embryologic systems

Primordium

Differentiates toward

Key regulator

Müllerian duct

Uterus, fallopian tubes, upper vagina

Regression induced by AMH from Sertoli cells

Wolffian duct

Epididymis, vas deferens, seminal vesicles

Maintenance promoted by testosterone

Slide 9 · Phenotypic sex: External genital anatomy

External genital appearance represents one endpoint of prenatal differentiation.

Androgen exposure, conversion to DHT and androgen receptor activity influence virilization.

Similar external phenotypes may arise through distinct molecular defects.

Atypical genital anatomy does not establish chromosomal or gonadal constitution.

Slide 10 · Discordance can occur at different levels

Chromosomes

46,XX or 46,XY constitution

Gonadal tissue

Ovary, testis, ovotestis or dysgenesis

Anatomy

Ductal and genital structures may be discordant

Slide 11 · Presentation varies by life stage

Prenatal: Unexpected chromosome–ultrasound discordance.

Newborn: Atypical external genitalia or bilateral nonpalpable gonads.

Childhood: Inguinal gonad, hernia, unusual endocrine features.

Adolescence/adulthood: Primary amenorrhea, atypical puberty or infertility.

Slide 12 · Historical terminology: What Robbins means

Historical term

Source-defining feature

Current interpretation

“True hermaphroditism”

Both ovarian and testicular tissue

Ovotesticular DSD

“Female pseudohermaphroditism”

Ovarian gonads with masculinized genitalia

Historically overlaps part of 46,XX DSD

“Male pseudohermaphroditism”

Testicular gonads with under-virilized genitalia

Historically overlaps part of 46,XY DSD

Slide 13 · Why historical labels are no longer preferred

The terms emphasize a binary “true/pseudo” scheme instead of mechanism.

They do not describe the full chromosomal, gonadal and anatomical spectrum.

Modern care favors the specific diagnosis and terminology acceptable to the individual.

Historical nomenclature remains relevant when interpreting older textbooks.

Slide 14 · Anatomical findings and identity are distinct

Chromosomal/gonadal/anatomical characteristics are biological observations.

Gender identity and lived experience cannot be inferred from karyotype or histology.

Clinical communication should avoid prejudging future identity or goals.

An individual’s preferred terminology may vary.

Slide 15 · Sex differentiation: Simplified timeline

Gonadal decision

Differentiation of bipotential gonad

Hormonal signal

AMH and testosterone, or their absence

Anatomic response

Ductal differentiation and external morphology

Slide 16 · Testis-determining molecular cascade

SRY commonly initiates a testis-promoting program in 46,XY embryos.

SOX9 is a major downstream regulator of Sertoli cell differentiation.

This is a gene network: Chromosomal complement alone is not deterministic.

SRY activation

SOX9-associated program

Sertoli cell differentiation

Slide 17 · Ovarian differentiation is an active process

Ovarian development is not simply a passive fallback from absent Y chromosome.

Multiple ovarian-promoting and testis-antagonizing pathways participate.

Gonadal phenotype reflects a balance of regulatory networks.

Disruption may produce partial gonadal differentiation or ovotesticular tissue.

Slide 18 · Sertoli cells drive Müllerian regression

Differentiated fetal Sertoli cells produce anti-Müllerian hormone (AMH).

AMH signaling promotes Müllerian duct regression.

Failure of production or receptor signaling can preserve Müllerian derivatives despite testes.

Fetal Sertoli cell

AMH secretion

Müllerian duct regression

Slide 19 · Leydig-cell testosterone stabilizes Wolffian ducts

Fetal Leydig cells synthesize testosterone.

Testosterone maintains Wolffian ducts, leading to internal male-typical derivatives.

Absent testosterone action permits duct regression even if testes are present.

Testicular steroidogenesis

Testosterone reaches tissue

Wolffian duct maintenance

Slide 20 · DHT is crucial for external virilization

5α-reductase type 2 converts testosterone into dihydrotestosterone (DHT).

DHT is important for male-typical external genital differentiation.

Impaired DHT production may spare Wolffian structures while changing external morphology.

Testosterone

SRD5A2: 5α-reduction

DHT-responsive external tissue

Slide 21 · Distinct hormones, distinct anatomic outcomes

Signal

Main developmental target

If signaling is deficient

AMH

Müllerian structures

Persistence of Müllerian derivatives

Testosterone

Wolffian derivatives

Reduced or absent Wolffian development

DHT + androgen receptor

External genital virilization

Under-virilization despite testicular tissue

Slide 22 · Absence of testicular signals: Expected pattern

Without AMH, Müllerian structures can persist.

Without sufficient testosterone, Wolffian derivatives regress.

Without substantial prenatal androgen action, external genitalia generally develop along a female-typical pathway.

These are developmental tendencies—not guarantees in complex DSD.

Slide 23 · Four-level integration: Two simplified pathways

Common 46,XX pattern

46,XX

Ovarian differentiation

No testicular AMH/T

Müllerian derivatives

Female-typical external anatomy

Common 46,XY pattern

46,XY with functional SRY

Testicular differentiation

AMH + testosterone

Wolffian derivatives

DHT-dependent virilization

Teaching schematic: Exceptions exist at every level

Slide 24 · Contemporary classification framework

46,XX DSD

Androgen excess; Gonadal or developmental variations

46,XY DSD

Gonadal differentiation, steroidogenesis or androgen-action conditions

Sex chromosome DSD

Mosaic or aneuploid complements with variable phenotypes

Ovotesticular DSD

Both ovarian and testicular tissue in the same individual

Slide 25 · 46,XX DSD: More than virilization

Common mechanism: Fetal androgen excess with ovarian gonads.

Less common mechanisms include altered gonadal differentiation.

The presence of an XX karyotype alone does not establish ovarian tissue.

The exact cause requires clinical, biochemical and genetic correlation.

Slide 26 · 46,XY DSD: Mechanisms at three levels

Gonadal formation may be impaired despite 46,XY constitution.

Testosterone/DHT synthesis or conversion may be altered.

Androgen receptor function may be reduced or absent.

The same broad genital appearance can arise through different defects.

Slide 27 · Sex chromosome variation and mosaicism

45,X/46,XY

Can involve asymmetric gonadal development and mixed gonadal dysgenesis

46,XX/46,XY

Rare mosaic/chimeric complements may coexist with ovotesticular tissue

Structural Y variants

Loss or relocation of relevant genomic segments alters differentiation

Phenotypic variability

Tissue mosaicism may not match a single peripheral blood result

Slide 28 · Historical versus modern organizing questions

Historical question

Modern diagnostic question

“Which sex is real?”

Which chromosomal, gonadal, hormonal and anatomical features are present?

“True or pseudo?”

Is ovarian tissue, testicular tissue, or both demonstrable?

“Male or female pseudo?”

What underlying developmental mechanism and specific diagnosis explain the phenotype?

“Correct the phenotype?”

What health needs, preferences, options and longitudinal support apply?

Slide 29 · Ovotesticular DSD: Defining criterion

Both ovarian and testicular tissue must occur in one individual.

Tissues may be separate gonads or coexist in one ovotestis.

External genitalia range widely; No single appearance is diagnostic.

The gonadal-tissue definition corresponds to Robbins’ historical “true hermaphroditism.”

Slide 30 · Ovotesticular DSD: Anatomic arrangements

Unilateral ovotestis

Combined tissue on one side, with varying contralateral tissue

Bilateral ovotestes

Ovarian and testicular components in both gonads

Separate gonads

An ovary on one side and a testis on the other

Internal anatomy

Müllerian structures may be present, absent or asymmetric

Slide 31 · Ovotesticular DSD: Tissue-level distinction

Tissue finding

Diagnostic implication

Ovarian follicles within gonadal tissue

Supports an ovarian component

Seminiferous tubules / testicular architecture

Supports a testicular component

Both tissue types in one gonad

Supports an ovotestis

Streak or indeterminate gonad alone

Insufficient to designate ovotesticular DSD

Slide 32 · Why a gonadal biopsy can be misleading

Ovarian and testicular components may be spatially heterogeneous.

A limited core can sample only one component.

Morphologic interpretation depends on age and tissue preservation.

Histology, imaging, cytogenetics and molecular findings must be integrated.

Slide 33 · Genetic diversity in ovotesticular DSD

46,XX is a documented chromosomal background, but not the only one.

Some cases involve SRY-associated rearrangements.

Alterations affecting SOX9 regulation, NR5A1 and other pathways are reported.

A negative single-gene result does not exclude the tissue-defined condition.

Slide 34 · Ovotesticular DSD: Practical clinical implications

Gonadal endocrine function may be asymmetric or change with age.

Puberty, menstrual function, fertility potential and anatomy vary widely.

Gonadal tumor considerations depend on specific tissue and genetic context.

Care requires individualized counseling rather than label-based assumptions.

Slide 35 · 46,XX virilization: Common causal chain

Enzyme defect

Impaired adrenal cortisol synthesis

Precursor diversion

Increased adrenal androgen production

Prenatal effect

Variable external genital virilization

Slide 36 · 21-hydroxylase deficiency: Central mechanism

CYP21A2 encodes adrenal 21-hydroxylase.

Impaired cortisol synthesis increases ACTH drive.

17-hydroxyprogesterone accumulates upstream of the enzymatic block.

Steroid precursors enter active androgen-producing pathways.

Slide 37 · Cortisol feedback explains adrenal hyperplasia

Reduced cortisol weakens negative feedback.

Pituitary ACTH secretion rises.

Sustained ACTH drive stimulates the adrenal cortex and excess steroid precursors.

Low cortisol

Increased ACTH

Adrenal growth + androgen excess

Slide 38 · Salt-wasting CAH is a neonatal emergency

Severe enzyme deficiency may also impair aldosterone synthesis.

Sodium depletion and volume loss can lead to dehydration, shock and death.

Potential presentations include vomiting, poor feeding and failure to thrive.

Low aldosterone

Renal sodium / water loss

Adrenal crisis risk

Slide 39 · 17-hydroxyprogesterone: Diagnostic significance

Elevated 17-hydroxyprogesterone supports 21-hydroxylase deficiency.

Interpretation is age-, gestation-, assay- and collection-time dependent.

Electrolytes and glucose assess urgent physiological consequences.

A positive newborn screen requires confirmatory clinical evaluation.

Slide 40 · 46,XX virilization: Alternative causes

Mechanism

Illustrative cause

Main clue

Adrenal androgen excess

21-hydroxylase deficiency

Elevated 17-hydroxyprogesterone

Other adrenal steroid defect

11β-hydroxylase deficiency

Hypertension may occur

Exogenous androgen exposure

Maternal androgen medication / exposure

Prenatal history

Altered gonadal differentiation

46,XX testicular/ovotesticular DSD

Discordant gonadal tissue / molecular findings

Slide 41 · Case: Neonate with virilized external genitalia

A newborn has labioscrotal fusion and a single perineal opening. Gonads are not palpable. On day 7, feeding worsens and vomiting begins.

Which potentially life-threatening condition must be considered immediately?

Which first-line physiology and biochemical measurements are urgent?

Slide 42 · Case resolution: Prioritize adrenal physiology

Classic salt-wasting congenital adrenal hyperplasia is a critical possibility.

Assess hydration, blood pressure, glucose and electrolytes without delay.

Collect endocrine tests as feasible without delaying stabilization.

Refer urgently to neonatal/endocrine specialists.

Slide 43 · 46,XY DSD: Location of the primary defect

Gonadal differentiation

SRY/SOX9-related mechanisms; Complete or partial gonadal dysgenesis

Steroid production

Defects in Leydig-cell function or testosterone synthesis

Testosterone → DHT

5α-reductase type 2 deficiency

Androgen response

Androgen receptor defects: Complete or partial insensitivity

Slide 44 · 46,XY gonadal dysgenesis: Tissue failure

Testicular differentiation may be absent or incomplete.

Dysgenetic gonads may fail to produce appropriate AMH and androgens.

Müllerian structures can persist when Sertoli-cell AMH action is absent.

Tumor risk is higher in some dysgenetic gonads containing Y material.

Slide 45 · Steroidogenic 46,XY DSD: Causal model

Testes may form despite inadequate androgen synthesis.

Reduced testosterone impairs Wolffian duct maintenance.

Reduced androgen substrate also limits DHT-dependent virilization.

Testis present

Insufficient steroid synthesis

Under-virilization ± duct effects

Slide 46 · 5α-reductase type 2 deficiency

Testosterone production can be adequate.

SRD5A2-associated impairment reduces testosterone-to-DHT conversion.

Internal Wolffian structures may be preserved while external genitalia are under-virilized.

Testosterone intact

Reduced DHT conversion

External genital under-virilization

Slide 47 · Puberty in 5α-reductase deficiency

Testosterone-dependent virilization may become more pronounced at puberty.

Severity and lived outcomes vary; The phenotype is not fixed by the neonatal examination.

Hormone ratios require age-appropriate interpretation and sometimes stimulation.

Molecular testing can establish the underlying enzymatic cause.

Slide 48 · Androgen insensitivity: Target-tissue failure

Testicular androgen production may be present.

Altered androgen-receptor function reduces tissue responsiveness.

Phenotype spans complete and partial androgen insensitivity.

Testosterone production

AR signaling impaired

Variable androgen target response

Slide 49 · Complete androgen insensitivity syndrome

46,XY individuals commonly have testes and female-typical external genitalia.

AMH action normally prevents uterine development.

Androgen-dependent Wolffian derivatives are reduced or absent.

Presentation may include inguinal gonad, absent uterus or primary amenorrhea.

Slide 50 · Partial androgen insensitivity syndrome

Residual androgen receptor activity produces a broad phenotypic spectrum.

Hypospadias, cryptorchidism and variable genital virilization may occur.

Morphology does not reliably quantify receptor function.

Endocrine and molecular evaluation distinguishes PAIS from synthesis defects.

Slide 51 · 46,XY DSD: Mechanism–anatomy comparison

Condition

Müllerian structures

Androgen effect

Gonadal dysgenesis

May be present when AMH production is impaired

Variable/low

5α-reductase type 2 deficiency

Usually absent if AMH is intact

DHT-dependent external effects reduced

Complete androgen insensitivity

Usually absent if AMH is intact

Absent target response

Testosterone biosynthetic defect

Usually absent if Sertoli function is intact

Reduced androgen availability

Slide 52 · Persistent Müllerian duct syndrome: Different defect

Testes and male-typical external genitalia may be present.

AMH synthesis or AMH receptor signaling is defective.

Müllerian structures persist despite otherwise masculinizing androgen action.

Demonstrates independence of ductal and external genital differentiation.

Slide 53 · Case: Adolescent with primary amenorrhea

A phenotypically female adolescent presents with primary amenorrhea. Pelvic imaging reports an absent uterus, and gonadal tissue is identified in the inguinal canal.

Which disorders belong in the differential diagnosis?

Which endocrine and genetic tests help distinguish them?

Slide 54 · Case resolution: Classify the mechanism

Complete androgen insensitivity is an important possibility, not a diagnosis from imaging alone.

Establish chromosome complement and evaluate hormone synthesis/action.

Review gonadal anatomy and any prior surgery or imaging.

Provide coordinated endocrinology, genetics and psychosocial care.

Slide 55 · Neonatal signs that warrant DSD assessment

Atypical genital anatomy or a single perineal/urogenital opening.

Severe hypospadias with a bifid scrotum or undescended testes.

Bilateral nonpalpable testes in a term newborn.

Discordance between prenatal genetic findings and genital anatomy.

Slide 56 · First neonatal decision: Exclude a crisis

Congenital adrenal hyperplasia can cause rapidly progressive salt loss.

Careful review of feeding, vomiting, hydration and circulation is urgent.

Investigations and specialist referral must not delay stabilizing treatment.

Recognize possible DSD

Check physiology / electrolytes

Urgent referral and treatment if unstable

Slide 57 · History: Targeted diagnostic clues

Ask about familial DSD, infertility, amenorrhea or unexplained neonatal deaths.

Record consanguinity and known pathogenic variants where applicable.

Review prenatal screening, maternal androgen exposure and fetal imaging.

Document neonatal symptoms of adrenal insufficiency.

Slide 58 · Physical examination: Document, do not presume

Document location and palpability of gonads.

Describe genital structures precisely; Record openings and fusion.

Assess hydration, blood pressure and other systemic features.

Avoid making a diagnosis or sex assignment solely from genital appearance.

Slide 59 · First-tier investigations: Purpose-driven

Investigation

Question addressed

Electrolytes / glucose

Is there life-threatening salt loss or hypoglycemia?

17-hydroxyprogesterone ± adrenal testing

Is classic CAH plausible?

Chromosome study and SRY assessment

What chromosomal constitution / gene status is present?

AMH, testosterone, gonadotropins

What is the evidence for gonadal and steroidogenic function?

Pelvic ultrasound

Are gonadal and Müllerian structures identified?

Slide 60 · Imaging: Strengths and limitations

Ultrasonography is commonly the initial examination of internal anatomy.

A nonvisualized uterus or gonad is not always truly absent.

MRI or targeted anatomical studies may clarify unresolved findings.

Imaging does not replace endocrine, genetic or histopathologic evidence.

Slide 61 · Genetic testing: An escalation strategy

Chromosome analysis detects numerical and some structural variations.

Directed SRY analysis may clarify atypical chromosomal–gonadal findings.

Multigene panels or exome sequencing may identify disease mechanisms.

Variants must be interpreted for pathogenicity and phenotype concordance.

Slide 62 · When histopathology contributes

Gonadal morphology can establish ovarian, testicular or dysgenetic tissue.

Sampling is not routine for every person with DSD.

A pathologist should consider maturation-related mimics of germ cell neoplasia.

Biopsy or gonadectomy decisions require individualized risk–benefit review.

Slide 63 · Integrated diagnostic reasoning

Phenotype does not identify one unique cause.

Combine clinical, hormonal, imaging and molecular findings.

Use histology when it changes diagnosis or clinical management.

Anatomy + clinical presentation

Endocrine + chromosome studies

Mechanism-specific diagnosis

Slide 64 · Gonadal tumor risk is subtype-dependent

Risk is influenced by dysgenetic gonadal tissue, Y-derived material and gonadal location.

Do not assign one cancer-risk percentage to all DSD conditions.

The tumor potential of CAIS differs from that of some dysgenetic gonads.

Surveillance and gonadal surgery decisions should be individualized.

Slide 65 · Care: Multidisciplinary and longitudinal

Paediatric endocrinology, genetics and relevant surgical specialists coordinate diagnostic care.

Psychological support and age-appropriate disclosure are integral.

Fertility, hormone needs and tumor surveillance vary by diagnosis.

Transition to adult services supports lifelong health decisions.

Slide 66 · Informed decisions and autonomy

Urgent medical treatment should be distinguished from elective anatomic interventions.

Current specialist guidance supports transparent shared decision-making.

Irreversible nonurgent procedures warrant particular attention to future autonomy.

Published evidence on long-term outcomes remains incomplete.

Slide 67 · Five clinicopathologic distinctions to retain

Gonad ≠ chromosome

SRY and gonadal network alterations create exceptions

Duct ≠ external genitalia

AMH and androgen signals have different targets

Ovotesticular ≠ dysgenetic

Both ovarian and testicular tissues require evidence

Urgency ≠ cosmetic anatomy

Adrenal salt loss is urgent; Appearance alone is not

Slide 68 · Integrated challenge: Classify before naming

A newborn has an undervirilized phallus and a palpable inguinal gonad. Pelvic ultrasound does not identify a uterus. Testosterone production appears adequate, but DHT action is uncertain.

Which endocrine pathways remain plausible?

What finding would distinguish inadequate DHT synthesis from AR dysfunction?

Slide 69 · Integrated challenge: Mechanism first

A palpable gonad and absent uterus suggest testicular tissue with Sertoli-cell AMH action.

Evaluate testosterone, DHT, timing of sampling and stimulation requirements.

Consider SRD5A2 deficiency versus partial androgen insensitivity and other causes.

Interpret biochemical evidence alongside molecular testing and clinical context.

Slide 70 · Final synthesis: Three rules for practice

Use histology to define ovotesticular tissue—not genital appearance.

Classify discordance along chromosome, gonad, duct and external anatomy.

Rule out endocrine emergencies; Then pursue individualized, multidisciplinary evaluation.

Slide 71 · Selected references

Foundational source

Supplementary specialist sources

Robbins, Cotran & Kumar. Pathologic Basis of Disease, 11th ed. (2026). Ch 5, p.152.

EAU Paediatric Urology Guidelines, section 20: DSD.

Historical terminology and four-level classification.

Ahmed et al. Clin Endocrinol. 2021;95:818–840.

Domenice et al. 46,XY DSD. Endotext (2022).

Endotext, Congenital Adrenal Hyperplasia; GeneReviews, 46,XX testicular DSD.