Adrenogenital Syndromes

Slide 1 · Adrenogenital Syndromes

Adrenal androgen excess • Congenital adrenal hyperplasia • Clinicopathologic interpretation

Pathology lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Distinguish neoplastic adrenal androgen excess from congenital adrenal hyperplasia (CAH).

Explain 21-hydroxylase deficiency through steroidogenesis and corticotropin feedback.

Differentiate salt-wasting, simple virilizing, and nonclassic presentations.

Relate biochemical defects to adrenal morphology, clinical features, and management.

Slide 3 · What is an adrenogenital syndrome?

Excess adrenal sex steroid activity can produce virilization or related disturbances of sexual differentiation.

Primary gonadal disorders can create similar phenotypes but represent a different etiologic source.

Adrenal-derived androgen excess is encountered in tumors or congenital enzyme defects.

Slide 4 · Where do adrenal androgens come from?

Adrenal precursors can become more potent androgens outside the adrenal gland.

Adrenal cortex

DHEA and androstenedione

Peripheral tissues

Androgen conversion

Testosterone

Androgenic tissue effects

Original editable mechanism schematic

Slide 5 · Adrenal and gonadal androgen regulation

Adrenal androgen production

Gonadal androgen production

Predominantly regulated by corticotropin (ACTH).

Regulated by the gonadal endocrine axis.

Can increase with persistent ACTH stimulation.

A distinct source that may mimic adrenal androgen excess.

Important in CAH and some adrenal neoplasms.

Must be distinguished clinically from adrenal disease.

Slide 6 · Two etiologic routes to adrenal androgen excess

Both routes can increase androgen effects, but their mechanisms differ.

Adrenocortical neoplasm

Steroid-secreting tumor

May cause virilization

May co-secrete cortisol

Congenital adrenal hyperplasia

Inherited enzyme deficiency

ACTH-driven adrenal enlargement

Androgen precursor diversion

Slide 7 · Virilizing adrenal tumors tend to be carcinomas

Among androgen-producing cortical tumors, virilizing carcinomas are more likely than adenomas.

The clinical hormonal phenotype does not establish tumor histologic subtype on its own.

Adrenocortical neoplasm is a separate etiologic category from CAH.

Slide 8 · Neoplastic androgen excess may be a mixed syndrome

Some virilizing tumors secrete glucocorticoids as well as androgens.

The coexistence of androgen excess and hypercortisolism creates a mixed hormonal phenotype.

A single adrenal neoplasm may account for apparently different endocrine syndromes.

Slide 9 · Hormonal behavior does not define tumor morphology

Virilizing adrenal tumors as morphologically like other cortical neoplasms.

Virilization is a functional secretion pattern rather than a unique histologic appearance.

Definitive neoplastic morphology belongs to the broader adrenocortical tumor assessment.

Slide 10 · CAH is a group of inherited steroidogenic disorders

CAH comprises several autosomal recessive metabolic disorders.

Each involves deficiency of a steroid-biosynthetic enzyme, usually affecting cortisol production.

Defects upstream in steroidogenesis change both hormone deficiency and precursor availability.

Slide 11 · Steroidogenesis has three major functional outputs

Simplified steroidogenic destinations

Cholesterol-derived precursors

Mineralocorticoids

Aldosterone

Salt and volume homeostasis

Glucocorticoids

Cortisol

Feedback on corticotropin

Sex steroids

Adrenal androgens

Virilizing potential

An enzymatic block can reduce one branch and divert precursors toward another.

Slide 12 · A biosynthetic block has two downstream effects

Reduced synthesis of hormones beyond the affected enzyme step.

Accumulation of steroid precursors upstream of that step.

Diversion of intermediates toward pathways that remain functional.

Slide 13 · 21-hydroxylase participates in two hormone pathways

Mineralocorticoid pathway

Progesterone

BLOCKED

21-hydroxylase

11-deoxycorticosterone

Aldosterone

Glucocorticoid pathway

17-hydroxyprogesterone

BLOCKED

21-hydroxylase

11-deoxycortisol

Cortisol

Original schematic; “blocked” denotes defective conversion in 21-hydroxylase deficiency.

Slide 14 · Block in the mineralocorticoid arm

The extent of aldosterone deficiency determines the salt-wasting risk.

Progesterone

21-hydroxylase

Defective conversion

Reduced deoxycorticosterone formation

Reduced aldosterone synthesis

Original editable mechanism schematic

Slide 15 · Block in the glucocorticoid arm

Loss of cortisol feedback triggers compensatory ACTH secretion.

17-hydroxyprogesterone

21-hydroxylase

Defective conversion

Reduced 11-deoxycortisol formation

Reduced cortisol synthesis

Original editable mechanism schematic

Slide 16 · The dual consequences of 21-hydroxylase deficiency

Cortisol branch

Aldosterone branch

Androgen branch

Impaired cortisol synthesis

May have severely reduced aldosterone

Precursors favor androgen formation

Reduced negative feedback on ACTH

Salt wasting when deficiency is severe

Virilization and hyperandrogenism

ACTH elevation drives adrenal hyperplasia

Volume/electrolyte derangements

Clinical effects vary with age and sex

Slide 17 · Cortisol deficiency releases the feedback brake

ACTH = corticotropin. This explains both enlargement and increased androgenic output.

Less cortisol

Less negative feedback

Higher pituitary ACTH

Persistent adrenal stimulation

Original editable mechanism schematic

Slide 18 · Why do the adrenal glands enlarge?

The trophic action of ACTH creates a characteristic structural response.

Cortisol enzyme defect

Sustained increase in ACTH

Bilateral cortical hyperplasia

Original editable mechanism schematic

Slide 19 · Why are androgens increased in CAH?

The metabolic rerouting occurs in the setting of persistent ACTH stimulation.

Precursor accumulation

Diversion to open androgen pathways

Excess androgen synthesis

Virilizing effects

Original editable mechanism schematic

Slide 20 · Hormonal deficit and hormonal excess coexist

Deficiency

Excess

Cortisol: Decreased feedback and impaired stress physiology

ACTH: Compensatory pituitary hypersecretion

Aldosterone: Deficient in some enzyme defects

Adrenal androgen output: Increased

May cause hypotension and salt wasting

May cause genital or pubertal androgenic effects

Slide 21 · Not every steroid enzyme defect behaves identically

Specific steroidogenic enzyme deficiencies alter different branches of the pathway.

Some defects reduce mineralocorticoids as well as cortisol.

Other defects may be incompatible with life or affect an isolated branch.

Slide 22 · CYP21A2 explains most congenital adrenal hyperplasia

Mutations in CYP21A2 cause 21-hydroxylase deficiency.

More than 90% of CAH cases to this enzyme defect.

The residual activity of the defective enzyme influences the clinical phenotype.

Slide 23 · Residual enzyme function explains a severity spectrum

These patterns form a clinical spectrum rather than unrelated disorders.

Severe enzyme loss

Very little hormone synthesis

Intermediate deficiency

Some aldosterone preserved

Partial deficiency

Milder, later androgen excess

Original editable mechanism schematic

Slide 24 · Three phenotypes of 21-hydroxylase deficiency

Classic salt-wasting

Severe cortisol deficiency

Severe mineralocorticoid deficit

Potential neonatal crisis

Simple virilizing

Reduced cortisol feedback

Mineralocorticoid sufficient to avert crisis

Progressive virilization

Nonclassic

Partial enzyme deficiency

Later onset

Milder androgenic features

Slide 25 · Classic salt-wasting CAH: Severe enzyme blockade

Little or no functional 21-hydroxylase blocks both affected branches of steroidogenesis.

Aldosterone and cortisol synthesis are profoundly impaired.

Androgenic excess coexists with potentially life-threatening hormone deficiency.

Slide 26 · Salt-wasting CAH: Failure of aldosterone synthesis

Mineralocorticoid deficiency explains fluid depletion rather than androgen excess.

21-hydroxylase deficiency

Severely impaired mineralocorticoids

Renal salt loss

Low circulating volume

Original editable mechanism schematic

Slide 27 · Salt-wasting CAH: Sodium and volume consequences

The ionic abnormality and hemodynamic compromise are causally linked.

Sodium loss

Hyponatremia

Fluid depletion

Hypotension

Original editable mechanism schematic

Slide 28 · Salt-wasting CAH: Potassium and acid–base effects

The severe classic form combines electrolyte and circulatory compromise.

Impaired aldosterone action

Hyperkalemia

Acidosis

Greater physiological instability

Original editable mechanism schematic

Slide 29 · An untreated salt-wasting crisis can be fatal

Immediate recognition is clinically crucial; The chain represents the severe phenotype.

Vomiting / dehydration

Salt and fluid losses

Hypotension

Cardiovascular collapse

Original editable mechanism schematic

Slide 30 · Why can salt-wasting become apparent only after birth?

Before delivery, maternal physiology maintains fetal electrolyte and fluid homeostasis.

Postnatal independence exposes the infant’s inadequate mineralocorticoid production.

An initially inconspicuous newborn examination does not rule out severe CAH.

Slide 31 · Classic CAH in newborns with female genitalia

Prenatal androgen excess can cause genital virilization evident at birth.

Clitoral enlargement and differences in sexual development are described.

External virilization may alert clinicians before severe salt loss appears.

Slide 32 · Classic CAH in newborns with male genitalia

The external genital examination may not identify the underlying enzyme defect.

Presentation with salt loss and hypotension commonly at 5–15 days.

An apparently typical genital examination must not delay assessment of dehydration and shock.

Slide 33 · Simple virilizing CAH preserves enough aldosterone

Mineralocorticoid production remains sufficient to avert a salt-wasting crisis.

Cortisol production is still inadequate to suppress ACTH appropriately.

Androgen excess therefore persists despite the relative preservation of salt balance.

Slide 34 · Simple virilizing CAH: Preserved salt balance

The term “simple virilizing” does not imply intact cortisol feedback.

Partial 21-hydroxylase activity

Aldosterone production sufficient

No major salt-wasting crisis

Original editable mechanism schematic

Slide 35 · Simple virilizing CAH: Continued androgen excess

A normal volume state does not remove the androgenic phenotype.

Reduced cortisol

Increased ACTH

Increased adrenal androgen output

Progressive virilization

Original editable mechanism schematic

Slide 36 · Virilization may be progressive in childhood

The clinical phenotype reflects cumulative androgen exposure.

Genital differences can be present from prenatal exposure.

Continuing excess androgen secretion produces additional masculinizing effects over time.

Slide 37 · Nonclassic CAH reflects partial enzyme deficiency

Residual 21-hydroxylase activity makes manifestations milder than in classic disease.

Clinical signs may first emerge later in childhood or after puberty.

Hyperandrogenism rather than neonatal adrenal crisis predominates.

Slide 38 · Nonclassic hyperandrogenism: Typical manifestations

Hirsutism may be a presenting complaint.

Acne reflects increased androgenic activity.

Menstrual irregularity may be the clue to an underlying steroidogenic defect.

Slide 39 · Routine newborn screens do not reliably find nonclassic CAH

That nonclassic cases are generally missed by routine neonatal CAH screening.

Diagnosis is usually made later through investigation of steroid biosynthesis.

A normal newborn screen does not exclude a mild enzyme defect.

Slide 40 · Clinical phenotypes: The decisive distinctions

Feature

Salt-wasting classic

Simple virilizing

Nonclassic

Enzyme impairment

Severe

Partial, clinically significant

Mild / partial

Mineralocorticoid effect

Insufficient; Salt loss

Enough to prevent crisis

Severe salt loss usually absent

Predominant concern

Neonatal collapse

Progressive virilization

Mild later hyperandrogenism

Onset

Usually infancy

Often early life

Later childhood / adulthood

Slide 41 · Clinical onset varies with the severity of the defect

Timing is one axis of CAH severity; Manifestations also depend on the affected hormone.

Perinatal period

Severe blockade

Childhood

Progressive androgen effects

Adulthood

Milder phenotypes

Original editable mechanism schematic

Slide 42 · Androgen excess in infants with female genitalia

Virilization may be present during fetal development.

Clinical findings range from clitoral hypertrophy to other differences in sexual development.

The degree of androgen exposure shapes the external phenotype.

Slide 43 · Androgen excess after puberty in females

Oligomenorrhea and other menstrual irregularities may occur.

Hirsutism and acne are frequent androgenic manifestations.

A mild later presentation is compatible with nonclassic steroidogenic deficiency.

Slide 44 · Androgen excess in prepubertal males

Excess adrenal androgen can enlarge the external genitalia.

Clinical features can mimic or cause signs of precocious puberty.

The absence of neonatal genital ambiguity does not exclude CAH.

Slide 45 · Androgen excess in older males

Oligospermia among possible manifestations.

Androgen excess can disrupt reproductive physiology despite apparently masculinized features.

Clinical expression changes with developmental stage.

Slide 46 · The adrenal cortex supports the medulla

Normal medullary function partly depends on adequate local glucocorticoid exposure.

Intra-adrenal glucocorticoids

Support for medullary catecholamine synthesis

Epinephrine / norepinephrine production

Original editable mechanism schematic

Slide 47 · Severe CAH may include adrenomedullary dysplasia

Severe salt-wasting 21-hydroxylase deficiency can impair adrenal medullary development.

Reduced intra-adrenal glucocorticoid exposure affects catecholamine secretion.

The disorder can therefore compromise both cortical and medullary physiology.

Slide 48 · Why can severe disease magnify hypotension?

These converging mechanisms increase the risk of circulatory collapse.

Mineralocorticoid loss

Fluid and sodium depletion

Cortisol deficiency

Impaired hormonal support

Medullary dysfunction

Reduced catecholamine response

Original editable mechanism schematic

Slide 49 · Gross pathology: Bilateral adrenal enlargement

Persistent ACTH stimulation leads to bilateral cortical hyperplasia.

The glands may become markedly enlarged; Up to 10–15 times normal weight.

Hyperplasia is a diffuse trophic response rather than an isolated androgen-producing tumor.

Slide 50 · Gross morphology: Thick, brown, nodular cortex

Schematic — not a gross pathology photograph

Thickened cortex

Bilateral cortical hyperplasia

Nodular brown cut surface

Brown color reflects lipid depletion.

Slide 51 · Microscopic morphology: Lipid-depleted compact cells

Schematic — not a histology micrograph

Compact cells

Eosinophilic cytoplasm; Depleted lipid

Intermixed clear cells

Residual lipid-containing cells

Slide 52 · Pituitary morphology is part of the feedback response

Reduced circulating cortisol removes negative feedback from corticotroph cells.

Most individuals with CAH show corticotroph hyperplasia in the anterior pituitary.

The pituitary change parallels the sustained elevation in ACTH.

Slide 53 · Link the structure to the pathophysiology

Morphological finding

Underlying mechanism

Bilateral adrenal cortical enlargement

Sustained trophic stimulation by ACTH

Brown, lipid-depleted cortex

Increased steroidogenic activity with reduced lipid stores

Compact eosinophilic cortical cells

Hyperplastic lipid-depleted population

Anterior pituitary corticotroph hyperplasia

Compensatory ACTH response to cortisol deficit

Slide 54 · Diagnostic warning: Ambiguous genitalia in a neonate

Congenital adrenal hyperplasia is an important consideration in any neonate with genital ambiguity.

The presentation may reflect prenatal adrenal androgen excess.

Evaluate concurrently for evidence of glucocorticoid and mineralocorticoid deficiency.

Slide 55 · Diagnostic warning: The vomiting infant

Vomiting, dehydration, and salt wasting may be the initial features of severe CAH.

Hyponatremia, hyperkalemia, acidosis, and hypotension reinforce the salt-wasting pattern.

Possible circulatory collapse makes this presentation a medical emergency.

Slide 56 · Diagnosis follows the steroidogenic defect

The clinical pattern directs attention to the affected hormone pathways.

Biochemical demonstration of abnormal steroidogenesis is central, particularly for nonclassic disease.

CYP21A2-related molecular testing can confirm the inherited etiology when indicated.

Slide 57 · Newborn detection: A critical distinction

Severe classic CAH

Nonclassic CAH

May be detected through neonatal metabolic screening.

Often escapes routine newborn screening.

Early identification can prevent severe salt-wasting consequences.

Evaluation usually follows symptoms of hyperandrogenism.

A screening program does not replace clinical assessment.

A normal neonatal result is not a lifetime exclusion test.

Slide 58 · Molecular testing can detect CYP21A2 abnormalities

CYP21A2 is the gene affected in common 21-hydroxylase deficiency.

Feasibility of molecular testing for antenatal detection.

Genetic identification complements—rather than replaces—the clinical and biochemical phenotype.

Slide 59 · Glucocorticoid therapy has two mechanistic effects

Providing glucocorticoids also suppresses the trophic drive behind androgen excess.

Exogenous glucocorticoids

Cortisol replacement

Less ACTH stimulation

Reduced excess steroid synthesis

Original editable mechanism schematic

Slide 60 · Salt-wasting CAH requires mineralocorticoid support

Glucocorticoid replacement alone does not directly restore severely deficient aldosterone activity.

Mineralocorticoid supplementation is needed in salt-wasting variants.

Clinical assessment must address both steroid deficiencies and androgen excess.

Slide 61 · Why outcomes improve with early recognition

Routine neonatal screening supports earlier identification of severe forms.

Genetic testing can identify CYP21A2 defects before birth when indicated.

Timely hormone replacement reduces the consequences of critical endocrine deficiency.

Slide 62 · Application case: Neonatal collapse

Clinical vignette

A newborn with male external genitalia develops vomiting, severe dehydration, and hypotension near the end of the first postnatal week. Laboratory evaluation reveals low sodium and high potassium.

Which CAH phenotype best explains the full presentation?

Slide 63 · Case interpretation: Classic salt-wasting CAH

The postnatal onset and electrolyte derangements point to severe mineralocorticoid deficiency.

Low cortisol permits persistent ACTH drive, but androgenic signs may not be obvious at birth in males.

The syndrome requires prompt recognition of life-threatening adrenal hormone deficiency.

Slide 64 · Application case: Delayed hyperandrogenism

Clinical vignette

A postpubertal patient presents with hirsutism, acne, and menstrual irregularity. There is no history of neonatal salt-wasting crisis. Investigation indicates an adrenal steroid biosynthetic abnormality.

Which end of the 21-hydroxylase deficiency spectrum is most consistent?

Slide 65 · Case interpretation: Nonclassic CAH

Later-onset, comparatively mild androgenic features favor nonclassic disease.

Partial enzyme deficiency permits sufficient steroidogenesis to avoid severe neonatal salt loss.

The biochemical steroidogenic abnormality helps distinguish this syndrome from other androgen excess causes.

Slide 66 · Differentiate CAH from an androgen-secreting tumor

Congenital adrenal hyperplasia

Adrenocortical neoplasm

Autosomal recessive inherited enzyme deficiency

Autonomous or neoplastic cortical steroid secretion

Cortisol deficiency leads to sustained ACTH

May co-produce cortisol and produce a mixed syndrome

Bilateral ACTH-driven cortical hyperplasia

Morphology follows cortical neoplasm patterns

Severe forms include salt-wasting physiology

Virilizing neoplasms are more often carcinomas

Slide 67 · Integrated causal model

21-hydroxylase defect → impaired cortisol synthesis → increased ACTH → bilateral adrenal hyperplasia.

Blocked steroidogenic reactions → precursor diversion → androgen excess and virilization.

Severe aldosterone deficiency → salt loss, electrolyte disturbance, and possible neonatal collapse.

Slide 68 · Three clinical principles to retain

Determine whether adrenal androgen excess is caused by CAH or a cortical neoplasm.

Separate androgenic manifestations from cortisol and aldosterone deficiency.

Recognize that clinical onset and severity vary with residual steroidogenic enzyme activity.

Slide 69 · Primary reference and scope

Robbins, Cotran & Kumar: Pathologic Basis of Disease

11th edition (2026), endocrine system chapter

Section: Adrenogenital Syndromes

Original teaching schematics; no patient-derived or synthetic diagnostic specimens.