Secondary Adrenocortical Insufficiency

Slide 1 · Secondary Adrenocortical Insufficiency

Mechanisms · morphology · clinicopathologic reasoning

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · What this lecture should enable

Localize hypoadrenalism along the hypothalamic–pituitary–adrenal axis.

Explain cortisol deficiency with preservation of aldosterone.

Predict adrenal morphology after sustained ACTH deprivation.

Interpret plasma ACTH and the timing of cosyntropin responses.

Separate secondary insufficiency from primary Addison disease.

Slide 3 · Secondary insufficiency: A failure of trophic drive

Upstream lesion

Pituitary, hypothalamic or pharmacologic cause

Reduced ACTH

Insufficient trophic stimulation of adrenal cortex

Hormonal deficit

Cortisol and adrenal androgen secretion decline

Clinical effect

Hypoadrenalism without typical aldosterone loss

The primary abnormality is reduced ACTH drive—not initial destruction of the adrenal cortex.

Slide 4 · Two broad mechanisms of adrenal hypofunction

Primary insufficiency

Adrenal cortical cells are destroyed or dysfunctional.

ACTH rises in response to inadequate cortisol.

Mineralocorticoid deficiency is often important.

Secondary insufficiency

ACTH output is deficient or suppressed.

Cortical tissue loses trophic stimulation.

Aldosterone remains normal or near normal.

Localization

Similar symptoms can arise from anatomically different lesions.

Slide 5 · Hypothalamic–pituitary–adrenal regulation

Hypothalamus

CRH signaling

Anterior pituitary

Corticotroph releases ACTH

Adrenal cortex

Cortisol secretion

Target organs

Metabolic and stress responses

Cortisol provides negative feedback to the hypothalamic–pituitary axis (physiologic context).

Slide 6 · Anatomical compartments of the adrenal gland

Adrenal cortex · schematic

Capsule

Zona glomerulosa

Zona fasciculata

Zona reticularis

Medulla

ACTH-responsive cortical zones

Zona fasciculata: Principal cortisol source

Zona reticularis: Major androgen source

Zona glomerulosa: Aldosterone; RAAS-regulated

Medulla: Catecholamines; Not cortical tissue

Schematic · not a clinical or histologic specimen

Slide 7 · Which cortical zones make which hormones?

Compartment

Major endocrine output

Principal control relevant here

Zona glomerulosa

Aldosterone

Renin–angiotensin–aldosterone system

Zona fasciculata

Cortisol

ACTH trophic drive

Zona reticularis

Adrenal androgens

ACTH trophic drive

Adrenal medulla

Catecholamines

Separate medullary regulation

Slide 8 · Why ACTH deficiency affects two cortical zones

Reduced ACTH

Loss of stimulation

Fasciculata

Cortisol output falls

Reticularis

Androgen output falls

Prolonged deficit

Both zones progressively atrophy

Aldosterone synthesis is relatively spared because glomerulosa function is largely ACTH-independent.

Slide 9 · Secondary versus tertiary terminology

Pituitary (secondary)

Corticotroph dysfunction decreases ACTH directly.

ACTH level is low or inappropriately normal.

Other anterior pituitary deficits may coexist.

Hypothalamic (tertiary)

Deficient releasing input can reduce ACTH.

Biochemical adrenal consequences overlap.

Robbins groups upstream hypoadrenalism together in places.

Vocabulary

The anatomic level should be stated explicitly when known.

Slide 10 · Where loss of ACTH originates

Intrinsic pituitary damage can eliminate corticotroph output.

Hypothalamic lesions may reduce the signals driving corticotrophs.

Exogenous glucocorticoids suppress endogenous corticotropin secretion.

Any of these routes may culminate in insufficient cortisol synthesis.

Unifying concept

Distinct upstream causes converge on reduced adrenal trophic stimulation.

Slide 11 · Etiologic families

Mechanism

Representative settings

Final common effect

Mass or infiltrative injury

Metastatic cancer; Other sellar masses

Loss of functional pituitary tissue

Inflammatory / infectious injury

Infection; Immune checkpoint hypophysitis

Corticotroph dysfunction

Ischemic injury

Infarction; Pituitary apoplexy

Abrupt or evolving hormone loss

Iatrogenic injury

Irradiation; Pituitary surgery

Damage to remaining gland

Hormonal suppression

Long-term exogenous glucocorticoids

Reduced endogenous ACTH

Slide 12 · Pituitary mass lesions: Tissue loss and hormone deficit

Sellar mass

Compression of normal anterior pituitary

Corticotroph loss

Lower functional ACTH output

Adrenal response

Reduced cortisol secretion

Clinical signal

Hypoadrenalism; Possibly other hormone deficits

Pituitary tumors and metastases can produce hypopituitarism by damaging non-neoplastic cells.

Slide 13 · Hypothalamic lesions: A different anatomical entry point

Hypothalamic injury

Tumors or metastases may affect releasing signals.

Irradiation can injure hypothalamic structures.

Inflammatory disorders may involve the region.

Endocrine consequence

Corticotrophs receive inadequate stimulation.

ACTH deficiency causes cortisol deficiency.

Concurrent posterior pituitary abnormalities may coexist.

Caution

Hypothalamic and pituitary lesions require an anatomical differential.

Slide 14 · Infections and inflammation can interrupt the axis

Inflammation

Pituitary/hypothalamic involvement

Hormone loss

Reduced ACTH secretion

Adrenal effect

Reduced cortisol synthesis

Presentation

Hypoadrenal symptoms with another causal clue

Examples include infectious and granulomatous disorders involving the axis.

Slide 15 · Pituitary infarction: From vascular event to endocrine loss

Vascular insult

Reduced anterior pituitary perfusion

Parenchymal injury

Ischemic necrosis of functional tissue

ACTH deficit

Compromised corticotroph secretion

Adrenal failure

Potential acute cortisol deficiency

Interpretation

Clinical severity depends on the degree and timing of pituitary tissue loss.

Slide 16 · Pituitary apoplexy can cause an acute endocrine emergency

Pathologic event

Sudden hemorrhage into pituitary tissue, often a PitNET.

Headache and ophthalmic symptoms may dominate initially.

ACTH-related consequence

Rapid loss of corticotroph function.

Hypotension, cardiovascular collapse or altered consciousness may follow.

Emergency feature

An acute pituitary event can lead to acute adrenal insufficiency.

Slide 17 · Sheehan syndrome: A postpartum causal sequence

Pregnancy

Anterior pituitary enlarges

Obstetric hemorrhage

Perfusion falls further

Pituitary infarction

Anterior lobe necrosis

Hypopituitarism

ACTH and other hormone deficiencies

The posterior pituitary is relatively spared because its blood supply differs.

Slide 18 · Irradiation and surgery: Two iatrogenic pathways

Irradiation

Radiation can damage residual non-neoplastic pituitary cells.

Hypothalamic injury can also impair endocrine signaling.

Pituitary surgery

Excision may remove functioning pituitary with the lesion.

Secondary hypoadrenalism can follow insufficient corticotroph reserve.

Mechanism

Treatment of intracranial disease can create a new endocrine deficiency.

Slide 19 · Immune checkpoint blockade: Hypophysitis pathway

Cancer immunotherapy

Immune checkpoint blockade

Immune injury

Pituitary inflammation (hypophysitis)

Corticotroph dysfunction

Reduced ACTH output

Adrenal insufficiency

Secondary hypoadrenalism

Robbins also notes that checkpoint blockade can cause primary adrenalitis: The site of injury matters.

Slide 20 · Checkpoint-related endocrine disease has two routes

Primary adrenalitis

Immune injury targets adrenal cortex.

Cortisol loss is due to primary gland dysfunction.

ACTH generally rises after cortisol falls.

Secondary hypophysitis

Immune injury targets pituitary function.

ACTH is deficient or inappropriately normal.

Aldosterone usually remains preserved.

Distinguish

Do not equate all checkpoint-associated hypoadrenalism with primary gland damage.

Slide 21 · Chronic glucocorticoids suppress endogenous ACTH

Exogenous steroid

Sustained glucocorticoid exposure

Feedback suppression

Endogenous ACTH secretion decreases

Cortical trophic loss

Fasciculata and reticularis regress

Functional consequence

Endogenous cortisol reserve is reduced

Long-term treatment can produce functional insufficiency even without a structural pituitary lesion.

Slide 22 · Steroid withdrawal: Why timing matters

Chronic exposure

ACTH output remains suppressed

Cortical atrophy

ACTH-dependent zones decrease

Rapid withdrawal

Exogenous support suddenly disappears

Stress or illness

Inadequate endogenous cortisol response

Interpretation

Abrupt withdrawal or failure to increase coverage during stress as crisis triggers.

Slide 23 · Isolated ACTH deficiency or panhypopituitarism?

Corticotropin deficiency can be isolated.

A broader lesion may reduce several anterior pituitary tropic hormones.

Coexisting TSH or gonadotropin deficiency can change clinical presentation.

The pattern of associated deficits can help localize the source lesion.

Diagnostic implication

Do not restrict pituitary evaluation to ACTH when broader dysfunction is suggested.

Slide 24 · Companion findings in broader anterior pituitary failure

Pituitary axis

Possible associated manifestation

ACTH

Hypoadrenalism

TSH

Central hypothyroid manifestations

LH / FSH

Amenorrhea, infertility, low libido

GH

Growth failure in children; Body-composition changes in adults

Prolactin

Failure of postpartum lactation

Slide 25 · Adrenal gland size reflects chronic trophic input

Sustained loss of corticotropin leads to reduced adrenal cortical mass.

The degree of shrinkage varies with duration and severity of deficiency.

Glands may become small and flattened yet remain yellow.

Residual lipid accounts for persistence of yellow coloration.

Morphologic clue

Atrophy is a downstream response to hormonal deprivation.

Slide 26 · Normal cortex versus ACTH-deficient cortex

Normal gland

Capsule

Zona glomerulosa

Zona fasciculata

Zona reticularis

Medulla

Reduced corticotropin drive

Capsule

Zona glomerulosa

Atrophic fasciculata

Atrophic reticularis

Medulla

Relative glomerulosa and medulla preservation

Schematic · not a clinical or histologic specimen

Slide 27 · What is preserved despite cortical shrinkage?

Relatively preserved

Zona glomerulosa, maintained by RAAS.

Adrenal medulla, a distinct endocrine compartment.

Progressively diminished

Zona fasciculata: Cortisol-producing tissue.

Zona reticularis: Adrenal androgen-producing tissue.

Pathology principle

Selective zonal atrophy mirrors dependence on ACTH.

Slide 28 · The morphologic mechanism is selective cortical atrophy

ACTH absent

No sustained trophic stimulus

Cellular regression

Cortical tissue diminishes

Narrow cortex

Thin ribbon on section

Relative sparing

Glomerulosa and medulla remain

Markedly reduced glands with a residual cortical ribbon composed largely of glomerulosa.

Slide 29 · Primary autoimmune destruction looks different

Primary autoimmune adrenalitis

Primary damage to steroidogenic cortical cells.

Cortex replaced by connective tissue in advanced cases.

Lymphoid infiltrates may be present.

Secondary ACTH deficiency

Small flattened glands, with residual lipid.

Atrophic ACTH-responsive cortical layers.

Medulla spared; Relative glomerulosa retention.

Do not conflate

Destruction of cortex ≠ atrophy from loss of trophic stimulation.

Slide 30 · Anatomic pattern offers etiologic clues

Process

Typical adrenal pattern

Reason

Secondary ACTH deficiency

Small, thin cortex; Medulla preserved

Loss of trophic stimulation

Autoimmune Addison disease

Cortical destruction; Residual scar/inflammation

Direct immune injury

Adrenal metastasis

Architecture obscured by neoplasm

Infiltrating tumor

Waterhouse–Friderichsen

Bilateral hemorrhagic destruction

Hemorrhage in severe sepsis

Slide 31 · Gross morphology is not a stand-alone diagnosis

Small adrenal glands are consistent with chronic reduced trophic drive.

Gross gland size does not establish the pituitary cause.

Endocrine testing and upstream clinical history are required.

Microscopy and hormone data should be interpreted together.

Interpretive limit

Morphology supports a mechanism; It does not uniquely localize the lesion.

Slide 32 · Clinical features begin with cortisol deficiency

Low ACTH

Decreased adrenal cortisol

Metabolic effects

Impaired glucocorticoid-dependent responses

Systemic symptoms

Weakness, fatigue, GI disturbance

Stress vulnerability

Poor reserve during infection or surgery

Secondary and primary insufficiency share many symptoms because both reduce cortisol availability.

Slide 33 · Nonspecific early symptoms can delay recognition

Progressive weakness and easy fatigability may precede diagnosis.

Anorexia, nausea, vomiting and weight loss can occur.

Symptoms overlap with many nonendocrine conditions.

Prior pituitary disease or long-term steroid use increases suspicion.

Clinical reasoning

A nonspecific symptom cluster becomes meaningful in the right endocrine context.

Slide 34 · Hypoglycemia links cortisol loss to metabolism

Physiologic loss

Glucocorticoid availability is reduced.

Hepatic gluconeogenic support is impaired.

Clinical consequence

Hypoglycemia may occur.

Metabolic manifestations need not be present in every patient.

Mechanism

Cortisol deficiency can impair glucose homeostasis.

Slide 35 · Why hypotension remains possible with intact aldosterone

Cortisol deficiency

Reduced glucocorticoid support

Physiologic stress

Insufficient adaptive response

Clinical consequence

Hypotension may occur

Severe deficiency

Risk of circulatory collapse

Preserved aldosterone reduces salt-wasting physiology, but does not eliminate crisis risk.

Slide 36 · Aldosterone is usually spared in central insufficiency

ACTH-deficient zones

Cortisol output decreases.

Adrenal androgen output decreases.

Fasciculata and reticularis atrophy over time.

Aldosterone pathway

RAAS signaling remains intact.

Glomerulosa function is normal or near normal.

Prominent hyperkalemia is therefore not expected.

Pattern recognition

Normal potassium supports—but cannot independently establish—central insufficiency.

Slide 37 · Why potassium differs between primary and secondary disease

Feature

Primary adrenal failure

Secondary ACTH deficiency

Aldosterone

Frequently reduced

Usually preserved

Sodium handling

Salt wasting may be prominent

Less primary mineralocorticoid loss

Potassium

Hyperkalemia may occur

Hyperkalemia generally absent

Underlying reason

Glomerulosa damage

RAAS remains functional

Slide 38 · Why hyperpigmentation is absent

Secondary disorder

ACTH output not elevated

POMC pathway

No excess pituitary precursor output

Melanocyte signaling

No characteristic stimulation pattern

Clinical finding

Addison-type pigmentation absent

In primary insufficiency, increased POMC/ACTH is linked to increased melanocyte-stimulating activity.

Slide 39 · Pigmentation as a localisation clue

Primary Addison disease

Loss of cortisol feedback raises ACTH/POMC.

Characteristic pigmentation may appear at pressure points and exposed skin.

Central insufficiency

ACTH is low or inappropriately normal.

Characteristic Addisonian hyperpigmentation is absent.

Important caveat

Absence of pigmentation alone is not sufficient to classify an individual patient.

Slide 40 · Adrenal androgen output also decreases

ACTH supports zona reticularis steroidogenesis.

Reduced trophic stimulation lowers adrenal androgen production.

This deficit can accompany cortisol deficiency.

It helps explain why central disease is not simply isolated loss of cortisol.

Clinical pattern

Robbins characterizes secondary hypoadrenalism by deficient cortisol and androgen output.

Slide 41 · Intercurrent stress can unmask inadequate reserve

Latent hypoadrenalism

Baseline cortisol production already limited

Added demand

Infection, trauma or surgery

Failed compensation

No sufficient cortisol increase

Acute crisis

Severe systemic instability

An acute adrenal crisis can supervene even when the initial disorder was insidious.

Slide 42 · Adrenal crisis is a clinical emergency

Warning manifestations

Intractable vomiting or abdominal pain.

Marked hypotension or vascular collapse.

Altered consciousness or coma.

Pathophysiologic setting

Stress-related cortisol demand exceeds reserve.

Corticotropin-deficient patients may be unable to respond.

Prompt corticosteroid therapy is lifesaving.

Emergency

Do not delay urgent treatment of suspected adrenal crisis for an elective diagnostic pathway.

Slide 43 · Laboratory localization: Cortisol plus ACTH

Observed pattern

Interpretation

Mechanistic explanation

Low cortisol + high ACTH

Suggests primary adrenal failure

Pituitary attempts to drive damaged cortex

Low cortisol + low ACTH

Suggests central insufficiency

Deficient corticotroph output

Low cortisol + “normal” ACTH

May indicate central insufficiency

ACTH is inappropriately normal for low cortisol

Potassium preserved

Compatible with central disorder

Aldosterone often preserved

Slide 44 · “Inappropriately normal” ACTH is not normal physiology

Cortisol is low

Negative-feedback drive rises

Expected response

ACTH should increase

Actual ACTH

Within reference interval

Interpretation

Inadequate response suggests central failure

A reference-range ACTH value can be abnormal in the context of low cortisol.

Slide 45 · Why a single cortisol value does not localize the lesion

What it establishes

Deficient circulating cortisol may be suspected.

Symptoms and other endocrine findings establish clinical relevance.

What is still needed

Concurrent ACTH to assess source of failure.

History of pituitary injury or glucocorticoid exposure.

Dynamic testing when clinically appropriate.

Core rule

The hormone deficit and the site of causation are different diagnostic questions.

Slide 46 · Cosyntropin challenges the adrenal cortex directly

Synthetic ACTH₁–₂₄

Cosyntropin administration

Adrenal stimulation

Direct cortical receptor activation

Measured response

Change in cortisol secretion

Interpretation

Available cortical functional reserve

Testing interrogates adrenal responsiveness—not the ability of the pituitary to make ACTH.

Slide 47 · Cosyntropin response depends on disease mechanism and duration

Clinical setting

Expected response

Why

Primary adrenal destruction

Reduced cortisol response

Functional cortical tissue destroyed

Long-standing central deficiency

May be reduced

Prolonged ACTH loss produces atrophy

Recent-onset central deficiency

May remain normal

Cortex retains responsiveness initially

Slide 48 · Temporal evolution changes cosyntropin findings

Before insult

Trophic function and cortisol reserve

New ACTH loss

Endogenous secretion decreases

Early stage

Cortex may still answer cosyntropin

Prolonged stage

Atrophy reduces stimulated response

Interpretation

A preserved response does not rule out recent central ACTH deficiency.

Slide 49 · A normal early stimulation test can be misleading

Cosyntropin bypasses upstream ACTH production.

Recently ACTH-deprived cortical cells may still respond normally.

A single adequate stimulated cortisol therefore cannot exclude recent central failure.

Interpret testing alongside chronology, ACTH and clinical context.

Diagnostic pitfall

Do not use recent-onset central disease and long-standing central disease interchangeably.

Slide 50 · Long-standing central disease can mimic primary failure on testing

Primary lesion

The adrenal cortex is intrinsically destroyed.

Exogenous ACTH cannot restore lost tissue.

Stimulated cortisol response is diminished.

Chronic secondary lesion

An initially intact cortex becomes atrophic.

Cosyntropin response also diminishes.

Concurrent endogenous ACTH helps distinguish mechanisms.

Discriminator

Interpret the basal ACTH level and history, not the stimulation result alone.

Slide 51 · Integrating three independent observations

Observation

Question answered

Potential limitation

Plasma cortisol

Is cortisol availability inadequate?

Does not alone identify source

Plasma ACTH

Is corticotroph response appropriate?

Must be interpreted with cortisol

Cosyntropin response

Can cortex respond to ACTH?

May be normal early in central disease

Other pituitary axes

Is there broader hypopituitarism?

May vary with lesion extent

Slide 52 · Case 1 · abrupt glucocorticoid cessation

Clinical vignette

A patient with prolonged glucocorticoid exposure stops treatment abruptly, then develops weakness, vomiting and hypotension during an intercurrent infection.

What links the medication history to impaired endogenous cortisol reserve?

Slide 53 · Case 1 · feedback suppression explains the failure

Long-term steroid

Endogenous ACTH suppression

Cortical atrophy

Decreased cortisol reserve

Sudden cessation

Loss of replacement effect

Acute illness

Demand exceeds endogenous supply

Primary pathology is suppression of the axis with secondary cortical atrophy.

Slide 54 · Case 2 · immune therapy and cortisol deficiency

Clinical vignette

During immune checkpoint blockade, a patient develops fatigue and hypotension. Cortisol is low, and ACTH is not appropriately elevated.

Which site of immune-related endocrine injury best fits this hormone pattern?

Slide 55 · Case 2 · use ACTH to distinguish immune targets

Hypophysitis — favored

Pituitary corticotroph impairment.

ACTH is low or inappropriately normal.

Low cortisol reflects central failure.

Adrenalitis — alternative

Direct cortical injury.

Low cortisol should provoke increased ACTH.

Potential mineralocorticoid involvement.

Answer

The hormone pattern favors central insufficiency due to hypophysitis.

Slide 56 · Case 3 · postpartum vascular injury

Clinical vignette

A patient experiences severe obstetric hemorrhage. Later, inability to lactate and symptoms of glucocorticoid deficiency raise concern for multiple anterior pituitary deficits.

Which pathologic process can connect these endocrine findings?

Slide 57 · Case 3 · pituitary infarction connects the deficits

Major hemorrhage

Anterior pituitary perfusion compromised

Ischemic necrosis

Loss of anterior pituitary cells

Multiple deficits

ACTH and prolactin can fall

Clinical syndrome

Hypoadrenalism plus lactation failure

Sheehan syndrome is postpartum necrosis of the anterior pituitary.

Slide 58 · Case 4 · normal cosyntropin after acute pituitary injury

Clinical vignette

Soon after pituitary apoplexy, cortisol is low with inadequate ACTH. A cosyntropin test nevertheless shows an apparently retained adrenal response.

Why is recent central insufficiency still a concern?

Slide 59 · Case 4 · functional reserve precedes atrophy

Early central lesion

Pituitary ACTH secretion can fail suddenly.

Adrenal cortex has not yet undergone major atrophy.

Test response

Injected ACTH can still stimulate intact cells.

Normal early response does not exclude the upstream lesion.

Answer

Test interpretation must incorporate duration since ACTH loss.

Slide 60 · Six integrated clinicopathologic distinctions

01

Central deficiency begins upstream of the adrenal cortex.

02

Reduced ACTH causes cortisol and adrenal androgen deficits.

03

Aldosterone is usually preserved through RAAS control.

04

Loss of pigmentation reflects lack of ACTH/POMC excess.

05

Long-standing disease causes selective cortical atrophy.

06

Low or inappropriately normal ACTH localizes the defect.

Slide 61 · High-yield comparison: Primary versus central failure

Dimension

Primary Addison disease

Central insufficiency

Causal location

Adrenal cortex

Pituitary / hypothalamic axis

ACTH

Elevated

Low or inappropriately normal

Cortisol

Low

Low

Aldosterone

Frequently low

Normal or near normal

Hyperkalemia

May be present

Generally absent

Hyperpigmentation

Characteristic possible

Not characteristic

Slide 62 · Applied interpretation: Three endocrine profiles

Profile A: Low cortisol + elevated ACTH + hyperkalemia → favors primary adrenal failure.

Profile B: Low cortisol + inadequate ACTH + preserved potassium → favors central failure.

Profile C: Low cortisol + inadequate ACTH + early normal cosyntropin response → central failure remains possible.

Interpretive principle

Read biochemical relationships, not isolated “normal” or “abnormal” flags.

Slide 63 · Final clinical reasoning sequence

Recognize symptoms or a stress-related adrenal crisis.

Identify predisposing pituitary, hypothalamic, immune-therapy or steroid exposures.

Interpret cortisol together with endogenous ACTH.

Account for chronicity before interpreting cosyntropin responses.

Assess additional pituitary deficits when clinically indicated.

Synthesis

Mechanism, morphology and hormone relationships should agree.

Slide 64 · Primary textbook reference

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026). Chapter 24: The Endocrine System.

Central topic: Secondary Adrenocortical Insufficiency; mechanism, hormones, morphology, and diagnostic tests.

Context: Hypopituitarism, adrenal anatomy, chronic primary hypoadrenalism, and acute adrenal crisis.