Pathology (dr.

Yabut)
Endocrine Patholgy

09 January 08

PITUITARY GLAND THE ADENOHYPOPHYSIS

-A pea-sized gland, weighs 0.5 gm & measures 1cm, - Five cell types in the adenohypophysis by
attached to the hypothalamus by a stalk immunostaining:
-Two lobes: anteroir & posterior 1- Lactotrophs (Mammotrophs): Prolactin (Prl) -
-Anterior lobe (adenohypophysis) acidophils.
-derived from Rathke’s pouch 2- Somatotrophs: growth hormone (GH) -
acidophils.
-contains cells that secrete trophic hormones
3- Corticotrophs: proopiomelanocortin (POMC)
that activate peripheral endocrine glands
precursor for adrenocorticotropic hormone
-hypothalamic releasing hormones are delivered (ACTH), melanocyte stimulating hormone (MSH),
via a portal venous system
β-endorphin, and β-lipotropin - basophils.
- Posterior lobe (neurohypophysis)
4- Thyrotrophs: thyroid stimulating hormone (TSH)
- derived from outpouching from floor of 3rd
- basophils.
ventricle
5- Gonadotrophs: follicle stimulating hormone
- has a separate blood supply
(FSH) & luteinizing hormone (LH) - basophils.
- consists of modified glial cells & axons
extending from the supraoptic & Hypothalamic Releasing Corresponding Anterior
paraventricular nuclei in the hypothalamus Hormone Pituitary Hormone(s)
- neurons in the supraoptic & paraventricular Gonadotropin Luteinizing Hormone
nuclei produce ADH & oxytocin Releasing Hormone (LH)
(GnRH) * Follicular Stimulating
- ADH & oxytocin are stored in axon terminals Hormone (FSH)
in the post. Lobe Growth Hormone Growth Hormone (GH)
Releasing Hormone
(GRH) *
Corticotropin Adrenocorticotropic
Releasing Hormone Hormone (ACTH)
(CRH) *
Thyrotropin Releasing Thyroid Stimulating
Hormone (TRH) * Hormone (TSH)
Dopamine ** Prolactin (PRL)
* stimulatory
** inhibitory

DISEASES OF THE ADENOHYPOPHYSIS

-⇑ function: Hyperpituitarism
-⇓ function: Hypopituitarism
-nonfunctional adenoma
-inflammatory lesions
-ischemic injury
-mass effects
-enlargement of sella turcica
-visual field defects (classically bitemporal
hemianopsia)
-⇑ intracranial pressure
-headache, blurring of vision
-nausea and vomiting

Pwets 1 of 13
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CAUSES OF HYPERPITUITARISM
1 - Primary hypothalamic disorders (rare)
2 - Primary Pituitary Hyperplasia (rare)
3 - Functioning carcinomas (extremely rare)
4 - Functioning Adenomas (MCC). Classified as:
1. Prolactinomas (Prl)
2. Somatotroph (GH) adenomas
3. Corticotroph (ACTH) adenomas
4. Gonadotroph (FSH/LH) adenomas
5. Thyrotroph (TSH) adenomas
HYPERPROLACTINEMIA (amenorrhea-
6. Pleurihormonal adenomas (GH+Prl).
galactorrhea syndrome)
Monoclonal but
The MC pituitary hyperfunction syndrome. Caused
polyhormonal, or mixed-cell adenomas.
by:
1- Prolactinomas;
-Prl secreting adenoma (sparsely granulated,
chromophobic)
-F/M >1, peak incidence 20-30 yrs. of age
-serum prolactin level > 300 ug/L is diagnostic
-Rx: surgery (transsphenoidal)
bromocriptine (dopamine receptor agonist)
radiation
2- Hypothalamic diseases. Hypothalamus normally
produces dopamine (Prl-inhibitory factor).
-head trauma, etc.
-stalk effect
3- Anti-dopaminergic drugs (phenothiazines,
haloperidol)
4- Estrogen therapy
5- Primary Hypothyroidism (⇑ TRH ⇒ ⇑ Prl)

Signs & Symptoms:

- women: galactorrhea, amenorrhea,
infertility, ⇓ libido
- men: ⇓ libido, impotence & rarely
galactorrhea &
gynecomastia

SOMATOTROPH ADENOMAS
Acromegaly;
-adult onset excess growth hormone (GH) ⇒
enlargement of the skull, facial bones, jaw, hands,
feet, soft tissues & organs.
-diabetes, hypertension, muscle weakness, arthritis,
gonadal dysfunction, cardiovascular disease
Gigantism;
-GH excess occurs in children (before closure of
epiphyses).
-generalized increase in body size
-disproportionately long arms and legs
 Pathology – Endocrine Pathology by Dr. Yabut Page 3 of 13

* Morphology: macroadenomas, composed of Pathologic Entity Low High

densely or sparsely granulated “acidophilic” cells, Dose Dose
strongly positive for GH by immunostains. ACTH Secreting – +
- 30% elaborate both GH and Prl (a mixed cell Pituitary Adenoma
adenoma or a single cell-type pleurihormonal Cortisol Secreting – –
adenoma). Adrenocortical
- 40% express the gsp oncogene Neoplasm
- GH acts indirectly by ⇑ hepatic secretion of ACTH Secreting – –
insulin-like growth factor-1 (IGF-1) Nonendocrine
- Diagnosis: Neoplasm
- ⇑ serum GH & IGF-1
- serum prolactin may be elevated OTHER FUNCTIONING ADENOMAS
- glucose suppression test Gonadotroph adenomas:
- imaging scans (MRI better than CAT scan) -majority produce FSH, some FSH & LH, rarely only
- Treatment: LH
- transsphenoidal surgery, octreotide -MC occur in middle-aged men & women
acetate, radiation -usually are macroadenomas
-symptoms MC related only to local mass effects
-may cause amenorrhea or galactorrhea, ⇓ libido in
men

Thyrotroph adenomas
-produce TSH ⇒ hyperthyroidism

HYPOPITUITARISM
• Caused by either hypothalamic or pituitary
lesions:
• Hypothalamic lesions: craniopharyngioma,
CORTICOTROPH ADENOMAS gliomas & teratomas; metastatic carcinoma,
- MC small basophilic microadenomas that secrete infections
ACTH • Pituitary lesions:
Cushing’s disease o MCCs are: nonsecretory adenomas, Sheehan’s
-⇑ ACTH ⇒ ⇑ secretion of cortisol from the adrenal syndrome, radiation or surgical ablation (of ≥
glands 75% of the gland)
- moon face, buffalo hump, truncal obesity, o LCCs are: metastatic carcinoma, inflammatory
abdominal striae disorders, infections, genetic defects (pit-1)
-diabetes mellitus, hirsutism and amenorrhea (ACTH • Effects:
stimulates androgen secretion) -Isolated hormone deficiencies (e.g. GH or LH)
-increased skin pigmentation (MSH is secreted with -Panhypopituitarism: in children ⇒ dwarfism &
pituitary ACTH) infantilism (retarded physical & sexual
-hypertension, muscle weakness development) & in adults ⇒ hypogonadism,
- Diagnosis:
hypothyroidism & hypoadrenalism
-24 hr urine for free cortisol & 17-
hydroxycorticosteroids
-plasma ACTH level
-dexamethasone suppression test
-MRI scan

Dexamethasone Suppression Test

 Pathology – Endocrine Pathology by Dr. Yabut
HYPOTHALAMIC (SUPRASELLAR) NEOPLASMS
1- Craniopharyngioma (MC)
2- Gliomas
3- Germ cell tumors
⇒ mass effect ⇒ hypopituitarism &/or
diabetes insipidus.
Craniopharyngioma:
-Accounts for 3- 5% of intracranial tumors
-MC in the 2nd & 3rd decades
-derived from vestigial remnants of Rathke’s pouch
-arise in hypothalamus, may encroach on optic
chiasm
-benign, contain epithelial elements, often cystic
with calcification
-rupture of cystic tumors ⇒ inflammatory reaction
NON-SECRETORY ADENOMAS
- 20% of pituitary adenomas
-MC in 4th decade of life
- May grow to a large size (macroadenomas = >1
cm).
- ⇒ local mass effect (headache & visual
disturbances), and panhypopituitarism
(hypogonadism, hypothyroidism &
hypoadrenalism).
Histologically:
-most consist of chromophobic cells or intensely
eosinophilic cells (oncocytomas)
-usually are sparsely granular
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-often
stain negative for hormones with
immunostains
SHEEHAN’S SYNDROME
= Post-partum ischemic necrosis of the anterior
pituitary.
Precipitated by obstetric hemorrhage or shock ⇒
destruction of ≥ 75% of the gland.
Pedisposing factors:
-Anterior pituitary doubles in size during
pregnancy
-low pressure portal system unable to ⇑ blood
supply
-abrupt onset of hypotension ⇒ hypoperfusion ⇒
infarction.
Morphology:
Early: gland is swollen, soft & hemorrhagic.
Later: replaced by a shrunken fibrous scar.
Effects:
Failure of lactation, amenorrhea, hypothyroidism,
hypoadrenalism & decreased skin pigmentation.
Posterior lobe: usually is not affected
POSTERIOR PITUITARY SYNDROMES
ADH Deficiency (Diabetes Insipidus):
-⇓ ADH ⇒ decreased reabsorption of free water
-urine of low specific gravity, with inability to
concentrate it
-polyuria, polydypsia and hypernatremia
-caused by hypothalamic or pituitary lesions;
idiopathic
-corrected readily by ADH administration.
Inappropriate ADH Secretion (SIADH):
-⇑ ADH ⇒ excessive reabsorption of free water
-oliguria, urine of high specific gravity, with
inability to dilute it, and hyponatremia
- due to a compensatory ⇑ in ANP ⇒ no
hypervolemia, no ⇑ BP and no peripheral edema
-neurologic dysfunction: most likely 20 to
hyponatremia
-MCC is ectopic ADH secretion by a small cell
carcinoma of the lung
-Rx: fluid restriction
THYROID GLAND
Embryology:
-the thyroid develops from the primitive pharynx
 Pathology – Endocrine Pathology by Dr. Yabut
-the developing thyroid is attached to the base of
the tongue by the thyroglossal duct
-the thyroid descends in the midline & assumes its
final position in the anterior neck below the larynx
-excessive descent gives rise to a substernal
thyroid & incomplete descent ⇒ ectopic thyroid
higher in the neck or tongue
-persistence of remnants of the thyroglossal duct
can ⇒ thyroglossal duct cyst
Physiologic Effects of
Thyroid Hormones
• ⇑ gluconeogenesis,
glycogenolysis,
lipolysis & ATPase’s
•
heat
⇒ ⇑ basal metabolic rate &
production
• ⇑ protein catabolism
• ⇒ muscle wasting, osteoporosis
•= a hypermetabolic state, caused by increased
HYPERTHYROIDISM
⇑ sympathetic activity
levels of circulating T3 & T4.
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Effects: nervousness, warm moist skin, fine
tremors, palpitations, rapid pulse, exophthalmos,
weight loss, heat intolerance, muscle atrophy &
weakness, osteoporosis
Most Common Causes: Graves’ disease, toxic
multinodular goiter, toxic adenoma
Less Common Causes:
-thyroiditis, struma ovarii, toxic carcinoma
-TSH-secreting pituitary adenoma
-overtreatment with thyroid hormone tablets
(factitious hyperthyroidism)
HYPOTHYROIDISM
= a hypometabolic state caused by deficiency of T3
& T4.
Cretinism (congenital hypothyroidism)
- Clinical: severe mental retardation; short
stature; coarse facial features, protruding tongue
- Causes:
-Endemic - due to dietary iodine deficiency
-Sporadic
-thyroid dysgenesis
-inherited defects in thyroid hormone
synthesis
-inherited peripheral tissue resistance to
thyroid hormone
Myxedema (hypothyroidism in adults)
- fatigue, lethargy, slowed speech, mental
sluggishness
- cold intolerance, weight gain, constipation
- ⇓ sweating, bradycardia
- accumulation of ECM substances
(glycosaminoglycans)
- coarsening of facial features, nonpitting
edema
Causes:
- MCC is Hashimoto’s thyroiditis.
- surgical ablation or radiation
- iodine deficiency
-
-
drugs (e.g. propylthiouracil, lithium)
idiopathic primary hypothyroidism
- hypothalamic & pituitary disorders
HASHIMOTO’S THYROIDITIS
- MCC of hypothyroidism in areas where iodine
intake is adequate
Clinically:
- seen predominately in middle-aged women
-hypothyroidism with painless enlargement of the
gland
-may have transient thyrotoxicosis early on
 Pathology – Endocrine Pathology by Dr. Yabut Page 6 of 13

-familial predisposition, associated with HLA-DR3 Therapy: β-blockers, propylthiouracil, potassium

or HLA-DR5 iodide, radioiodine ablation, surgery

Pathogenesis:
-defective function of thyroid-specific suppressor
T cells ⇒ emergence of helper T cells reactive
with thyroid antigens
-helper T cells stimulate B cells to secrete
antithyroid antibodies, directed against: thyroid
peroxidase, TSH-receptors, iodine transporter, &
thyroglobulin, etc.
-thyroid injury is mediated by complement fixing
cytotoxic GOITER
antibodies, ADCC & CD8+ cytotoxic cells = enlargement of the thyroid, MC manifestation of
thyroid disease
- ⇓ hormone synthesis ⇒ ⇑ TSH ⇒ hyperplasia &
hypertrophy of follicular cells ⇒ gross enlargement

Diffuse nontoxic goiter:

-endemic
-iodine deficiency
-goitrogens (e.g. cabbage, cauliflower,
turnips, cassava root)
GRAVES’ DISEASE -sporadic
Clinical: -goitrogens
-MCC of hyperthyroidism, peak incidence 20-40 -hereditary defect in thyroid hormone
y/o synthesis
-a disease of females (F/M 10:1), affects 1-2% of -Clinical: most patients are euthyroid
women in US
-hyperthyroidism, symmetrical thyroid
MULTINODULAR GOITER
= nodular enlargement, derived from diffuse goiter
enlargement
- both monoclonal & polyclonal nodules
-opthalmopathy and dermopathy (pretibial
myxedema) (adenomatous goiter)
-familial predisposition, associated with HLA-B8 &
Clinical:
-most patients are euthyroid
HLA-DR3
-mass effects: compression of trachea, vessels &
-Laboratory values: ⇑ T3 & T4, ⇓ TSH and ⇑
nerves, & dysphagia
radioactive iodine uptake
-hyperthyroidism (toxic multinodular goiter)
Pathogenesis:
-An abnormality in T-suppressor cells ⇒ T-helper
-due to a hyperfunctioning nodule
cells that react to thyroid Ag’s ⇒ elaboration of B- -not accompanied by opthalmopathy or
cell clones capable of producing autoantibodies dermopathy
reactive with TSH receptors. * Morphology: massive enlargement (up to >2000
-IgG antibodies directed against TSH receptors,
gm), nodules, with a mixture of hyperplastic &
dilated follicles, involutional changes: hemorrhage,
act as agonists ⇒ ⇑ thyroid hormone secretion.
fibrosis, calcification & cystic degeneration
- The autoantibodies were originally called long
acting thyroid stimulator (LATS), because the
peak secretion of thyroid hormone occurs 16
hours after the exposure of thyroid tissue to
antibody, compared with 2 hours for TSH.
 Pathology – Endocrine Pathology by Dr. Yabut Page 7 of 13

-Peak incidence: 3rd-5th decades, F > M.

-Gene rearrangement on chromosome 10 ⇒
constitutive expression of tyrosine kinase domain of
RET protooncogene ⇒ papillary thyroid carcinoma
oncogene (RET/PTC)
- Often multifocal, spreads to lymph nodes in 50%
of cases, but distant spread in only 5%.
* Gross: unencapsulated,infiltrative, often cystic
with foci of fibrosis & calcification.
* Histology: papillary fronds, empty looking nuclei
THYROID NEOPLASMS “Orphan Annie eye”, nuclear grooves &
- Solitary nodules are more likely to be neoplastic. psammoma bodies.
- Nodules in younger patients (< 40 years) & in * Variants: encapsulated, follicular, tall cell
males are more likely to be neoplastic. * Prognosis: 90% survival at 20 years.
- Most neoplasms (>90%) are benign (adenomas).
- Functioning (hot) nodules on scintiscans are
usually benign
-Up to 10% of cold nodules are malignant
- Diagnosis can be made by fine needle aspiration
biopsy, or else by surgical excision biopsy.
THYROID ADENOMA
- adenomas account for > 90% of thyroid tumors
-thyroid adenomas are not premalignant
Gross: a sharply demarcated solitary nodule
Histology: a fibrous capsule separates the
neoplastic tissue from the surrounding
compressed gland. Patterns may be: trabecular
(embryonal), microfollicular (fetal) macrofollicular
and Hurthle cell (oncocytic) adenomas
- most commonly cold (nonfunctioning) on RI-scan
-rarely hot (functioning) & may cause
hyperthyroidism

FOLLICULAR CARCINOMA
- peak incidence: 5th-6th decades, F > M.
-incidence is ⇑ in areas of dietary iodine deficiency
* Gross: varies from well circumscribed to
extensively invasive
* Histology: MC small uniform follicles containing
THYROID CARCINOMA colloid
- uncommon in the US (~ 1.5% of all cancers). with capsular and vascular invasion (sure sign of
- major risk facrtor is exposure to radiation malignancy).
Variants include: * Variants: trabecular, Hurthle cell
1- papillary carcinoma 80% - spreads widely to distant organs: bones, lungs,
2- follicular carcinoma 15% liver, etc.
3- medullary carcinoma 5% - tumor tissue may take up radioactive iodine
4- anaplastic carcinoma rare -patients often Rx’ed postop with thyroid
hormones to ⇓ TSH
PAPILLARY CARCINOMA
* Prognosis: depends on tumor stage, 25 to 45% 10-
-MC form of thyroid Ca
yr survival rate for widely invasive tumors
 Pathology – Endocrine Pathology by Dr. Yabut Page 8 of 13

situated in close proximity to the upper and lower

poles of each thyroid lobe
- Histology: composed of chief cells (the majority)
and fat cells. The chief cells may undergo
transition to oxyphil cells (mitochondria), and
water clear cells (glycogen).
- chief cells secrete PTH
-secretion of PTH is regulated by the level of free
Ca++
-⇑ PTH secretion ⇒ ⇑ serum Ca++ by:
1. increasing synthesis of 1,25-(OH)2D, thus
enhancing
absorption of calcium from GIT.
2. activating osteoclasts ⇒ mobilizing
calcium from bone
MEDULLARY CARCINOMA
3. increasing renal tubular reabsorption of
- Neuroendocrine tumor of C cells, secrete
calcium while increasing urinary phosphate
calcitonin
excretion
-May also secrete: CEA, serotoin, somatostatin, VIP,
-Causes of hypercalcemia:
ACTH, etc.
- autonomous PTH hypersecretion
- Sporadic or familial (associated with MEN IIa & IIb,
- osteolytic metastases
etc., in
- PTH-related protein (PTHrP)
20% of cases)
- Familial cases are associated with germ line
mutations in RET
* Gross: sporadic cases: discrete tumor in one lobe,
peak incidence 5th-6th decades. MEN-associated:
multicentric & bilateral , peak 3rd-4th decades
* Histology: cell nests or trabeculae, amyloid
deposits in the stroma, C cell hyperplasia, + for
calcitonin, chromogranin, - for thyroglobulin
* Prognosis: overall 5-yr survival rate is 60 to 80%,
survival rates are better in familial cases due to
screening programs, serum calcitonin & CEA
levels are monitored post-op
PRIMARY HYPERPARATHYROIDISM
= autonomous hypersecretion of PTH.
- Accounts for up to 90% of cases of
hypercalcemia.
- Peak incidence 6th decade & older, F > M.
- Most cases are sporadic, but few cases are
familial (associated with MEN I & MEN IIA)
Causes:
1- Parathyroid adenoma (80%),
2- Primary hyperplasia (15%),
3- Carcinoma (<5%)
* Morphology:
PARATHYROID GLANDS • Adenoma
- There are usually four glands (they can be as -solitary & encapsulated, may consist of any of
many as 12), weighting 30 to 40 mg each, the 3 cell types
-remaining glands are normal to ⇓ in size
 Pathology – Endocrine Pathology by Dr. Yabut
-may be in an ectopic location
• Hyperplasia
-classically all 4 glands are involved
-may be nodular or diffuse
• Carcinoma
-solitary, dense capsule, may exceed 10 gm
-cytologic features are not reliable, presence of
invasion
or metastases required to make Dx
* Clinical Features:
- asymptomatic
- 90% are asymptomatic & discovered on
routine blood tests
- Ca++ & PTH levels are ⇑
- symptomatic
- 10% are symptomatic
- osteitis fibrosa cystica
- bone pain, pathologic Fx’s
- ⇑ bone resorption with expansile
areas (brown tumors)
- nephrolithiasis
- metastatic calcification
- GI Sx’s: constipaton, nausea, peptic ulcers,
pancreatitis
- CNS Sx’s: depression, lethargy, seizures
- NM Sx’s: weakness, fatigue
SECONDARY HYPERPARATHYROIDISM
= Compensatory hypersecretion of PTH due to
hypocalcemia
-renal failure
-vit. D deficiency
* Morphology:
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-hyperplasia of all (4) parathyroid glands
-skeletal changes of “renal osteodystrophy”
-metastatic calcification
* Clinical: few cases develop “tertiary”
hyperparathyroidism, looks identical to primary
hyperplasia
HYPOPARATHYROIDISM
= PTH deficiency & hypocalcemia
-neuromuscular irritability (tetany): carpopedal
spasm, laryngospasm, mental status changes,
convulsions
-cardiac conduction abnormalities
-calcification of the eye lens (cataract)
-calcification of the basal ganglia (Parkinsonism), ⇑
ICP (headache & papilledema).
-MCC: surgical excision of all glands (during total
thyroidectomy).
-LCC: congenital parathyroid agenesis (DiGeorge’s
syndrome), primary (idiopathic) atrophy -
autoimmune damage
-Lab. data: ⇓ serum Ca++ & ⇓ serum PTH level.
PSEUDOHYPOPARATHYROIDISM (PHP)
= Hypocalcemia and hyperphosphatemia, with:
-⇑ serum levels of PTH with hyperplasia of the
parathyroid glands
-no osteitis fibrosa cystica
-no vitamin D deficiency or renal failure.
* Pathogenesis: end-organ resistance to PTH, i.e.
kidneys & bone do not respond to PTH
stimulation.
* Clinical Features: similar to hypoparathyroidism
(tetany, etc.)
o PHP type 1 - ⇓ cyclic AMP response to PTH
(deficiency of Gsα ) short stature, round
face, short neck, short metacarpals &
metatarsals (Albright hereditary
osteodystrophy).
o PHP type 2 - normal cyclic AMP response to
PTH, but with ⇓ response to cyclic AMP,
phenotypically normal
 Pathology – Endocrine Pathology by Dr. Yabut
PSEUDOPSEUDOHYPOPARATHYROIDISM
- In PHP type 1, other family members may exhibit
the physical features of Albright hereditary
osteodystrophy (short stature, round face, short
neck, short metacarpals & metatarsals) but are
metabolically normal, with normal serum calcium
& normal PTH, i.e. false (pseudo)
pseudohypoparathyroidism.
ADRENAL GLAND
- Composed of two distinct units: steroid secreting
cortex & catecholamine producing medulla
- In the adult, the normal adrenal weighs 4 gm.
- The cortex consists of three functional zones:
1 - zona glomerulosa
2 - zona fasciculata (75% of the cortex)
3 - zona reticularis
- The cortex secretes three types of steroid
hormones:
1 - mineralocorticoids (aldosterone) - zona
glomerulosa.
2 - glucocorticoids (cortisol) - zona
fasciculata mainly.
3 - sex steroids (testosterone) - zona
reticularis mainly.
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Cortisol:
-regulated by ACTH (& hypothalamic CRH)
-inhibits release of CRH & ACTH
-circulates in the blood bound to plasma proteins
-free unbound cortisol is physiologically active &
enters target cells by diffusion
-binds to cytoplasmic receptors, then translocated
into the nucleus where it binds to hormone-
responsive elements altering expression of specific
genes.
* Biologic effects:
-⇑ gluconeogenesis & ⇓ uptake of glucose by fat &
muscle
-⇓ protein synthesis & ⇑ protein degradation
-⇑ vascular tone & some mineralocorticoid
activity
-anti-inflammatory & immunosuppressive effects
Aldosterone:
- Accounts for 95% of mineralocorticoid activity.
-regulated by renin-angiotensin & potassium levels.
-aldosterone promotes reabsorption of sodium and
excretion of potassium.
-excess aldosterone ⇒hypernatremia &
hypokalemia ⇒ hyper-volemia ⇒hypertension.
Testosterone:
-Excess testosterone in females causes
defemenization & virilization; (hirsutism, acne,
amenorrhea, clitoral enlargement, atrophy of the
breasts & uterus, deepening of the voice & frontal
balding).
 Pathology – Endocrine Pathology by Dr. Yabut Page 11 of 13

-In boys, excess testosterone leads to precocious * Diagnosis: 24 hr urine free cortisol, plasma ACTH,
puberty. Dexamethasone Suppression Test

DISEASES OF ADRENAL CORTEX
Hyperfunction (hyperadrenalism):
- Cushing’s syndrome
- Hyperaldosteronism
- Adrenogenital syndromes
Hypofunction (hypoadrenalism):
- Acute (e.g. Waterhouse-Friderichsen
Syndrome)
- Chronic:
- primary (due to adrenal cortical
insufficiency, e.g. Addison’s disease)
- secondary (due to ACTH deficiency)
- tertiary (rarely - due to hypothalamic CRH
deficiency).
PRIMARY HYPERALDOSTERONISM
= excessive secretion of aldosterone independent
of renin-angiotensin system.
* Features: hypervolemia, hypokalemia,
hypertension, low renin
* Causes:
-MCC is aldosterone-secreting adenoma (Conn’s
syndrome) in 80% of cases
-Bilateral idiopathic hyperplasia (? due to an
abnormal secretagogue)
-Glucorticoid-suppressible hyperaldosteronism:
hybrid cells produce both cortisol & aldosterone,
⇑ aldosterone under influence of ACTH,
suppressible by administration of
dexamethasone
* Prognosis: adenomas are curable by surgery.

ADRENOGENITAL SYNDROMES
Adrenogenital syndromes (ambiguous genitalia &
virilism in females, and precocious puberty in
males) can be caused by:
1- Androgen-secreting adrenal cortical neoplasms.
CUSHING’S SYNDROME 2- Congenital Adrenal Hyperplasia (CAH):
Etiology: -corticosteroid biosynthetic defect
1- Exogenous: high dose cortisone therapy (MCC). -MC 21-hydroxylase deficiency (90% of cases;
2- Pituitary hypersecretion of ACTH (Cushing’s autosomal recessive) ⇒ ⇓ cortisol ⇒ ⇓
disease), accounts for 70% of endogenous feedback inhibition of ACTH ⇒ ⇑ ACTH levels
hypercortisolism. Associated with
⇒ bilateral adrenocortical hyperplasia
hyperpigmentation of the skin (↑ MSH).
-aldosterone synthesis is MCly affected as well
3- Autonomous hypersecretion of cortisol by an
⇒ salt wasting adrenogenitalism (⇓ Na+, ⇑ K+,
adrenal adenoma, carcinoma or primary
hypovolemia)
hyperplasia (i.e. ACTH independent).
-⇑ production of androgens
4- Ectopic production of ACTH or CRH by
nonendocrine neoplasms (bronchogenic small cell
carcinoma).
* Clinical features: truncal obesity, moon face,
hirsutism, cutaneous striae, muscle weakness,
osteoporosis, hypertension & hyperglycemia;
Changes are reversible if the cause is corrected.
* Morphology:
•Cushing’s disease: ACTH is elevated ⇒ adrenals
are bilaterally hyperplastic. Changes are the
same with ectopic ACTH or CRH.
•Adrenocortical neoplasms: uninvolved adrenal
cortex is usually atrophic due to ACTH
suppression.
•Adenomas are small & cytologically bland
appearing
•Carcinomas are large & often anaplastic
 Pathology – Endocrine Pathology by Dr. Yabut Page 12 of 13

-Composed of specialized neuroendocrine

(chromaffin) cells, and is the major source of
catecholamines: epinephrine & norepinephrine.
-Chromaffin cells secrete catecholamines in
response to signals from preganglionic sympathetic
nerve fibers.
-These cells can also secrete a wide variety of
bioactive amines and peptides, such as: histamine,
serotonin, & neuropeptide hormones.
-Clusters of similar neuroendocrine cells form the
extra-adrenal paraganglia - closely associated with
the autonomic nervous system.
-The branchiomeric (carotid bodies) & intravagal
paraganglia are parasympathetic, and the
aorticosympathetic (organs of Zuckerkandl) are
sympathetic.

PHEOCHROMOCYTOMA
ACUTE ADRENOCORTICAL INSUFFICIENCY
= neoplasm composed of chromaffin cells that
MCC is sudden withdrawal of corticosteroids in
secretes catecholamines (0.1 - 0.3 % of all cases of
cases of long-term steroid therapy, or destruction
hypertension)
of adrenals by massive hemorrhage
* The “10 %” tumor:
Waterhouse-Friderichsen syndrome:
•10 % extra-adrenal
-overwhelming meningococcal septicemia
-DIC with widespread purpura (esp. skin) •10 % familial
-rapidly progressive hypotension ⇒ shock •10 % in children
-massive bilat. adrenal hemorrhage ⇒ acute •10 % bilateral in sporadic cases, but 70%
adrenocortical insufficiency bilat.in familial cases
-? causes of adrenal hemorrhage: DIC, endotoxin- •10 % malignant in adrenal cases, but up to 40%
induced vasculitis, bacterial seeding of small malignant in extra-adrenal cases
vessels * Clinical effects: hypertension (paroxysmal),
-high mortality rate tachycardia,
arrhythmias, tremors, sweating, sense of
CHRONIC ADRENOCORTICAL INSUFFICIENCY apprehension,
* Primary (adrenal) or secondary attacks can be fatal
(hypothalamic/pituitary): * Diagnosis: 24 hour urine for catecholamines; or
Primary (Addison’s disease): MCC: metanephrines & vanillylmandelic acid (VMA)
autoimmune adrenalitis; tuberculosis,
metastatic cancers (⇒ destruction of ≥ 90% of
the cortex) ⇒ decreased cortisol & aldosterone,
with feed-back elevation of ACTH (+ MSH) ⇒
hyperpigmentation of skin, ⇑ K+, ⇓ Na+, ⇓ BP,
weakness, anorexia, N&V, hypoglycemia
Secondary: to hypothalamic or pituitary lesions
associated with decreased ACTH ⇒ bilateral
adrenal cortical atrophy, sparing the zona
glomerulosa (skin color is pale and aldosterone
is normal, i.e. no sodium or potassium
abnormalities).
ADRENAL MEDULLA
 Pathology – Endocrine Pathology by Dr. Yabut Page 13 of 13

plus
4- Ganglioneuromas of the skin, eyes and
mucous membranes of the mouth, GI tract,
respiratory tract & bladder (100%)
5- Marfanoid body habitus (65%)
-------------------------------------------------------------------------
-
Aanhin pa ang damo,
Kung sayo plang, may tama na ako?
I list my number…. Can I have yours?
Nagpapacute kba? Kc umeepekto eh!
Kulangot kba? Kasi I wanna take you out.
Hi, I’m yours, can I call you mine?

--- galing sa old trans ng acute abdomen! just to

have some good memories to remember about the
MULTIPLE ENDOCRINE NEOPLASIA: exam. hehehe

MEN I (Wermer’s Syndrome) LOVE is just a word until someone you meet gives it
- heritable disorder caused by loss of a tumor a proper meaning. Happy Valentines! ööö
suppressor gene on chromosome 11.
1. Parathyroid hyperplasia or adenoma (95%) ⇒ ⇑
Ca++
2. Pancreatic Islet Cell tumors (75%) ⇒ excessive
secretion of:
- gastrin ⇒ peptic ulcers (Zollinger-Ellison
syndrome)
- insulin ⇒ hypoglycemia
- serotonin ⇒ carcinoid syndrome
- VIP ⇒ watery diarrhea
3. Pituitary adenoma (66%); MC prolactinoma,
also GH & ACTH producing adenomas

MEN IIA (Sipple’s Syndrome)

- inherited mutation in the RET protooncogene on
chromosome 10.
1. C cell hyperplasia or Medullary thyroid
carcinoma (100%)
2. Pheochromocytoma (50%), often bilateral and
may arise in the extra-adrenal paraganglia
3. Parathyroid hyperplasia or adenoma (25%)

MEN IIB (Gorlin’s Syndrome)

-inherited mutation in the RET protooncogene on
chromosome 10, different from that seen in MEN IIA
-neoplasms are as in MEN IIA:
1- C cell hyperplasia or Medullary thyroid
carcinoma (100 %)
2- Pheochromocytoma (34%)
3- Parathyroid hyperplasia or adenoma (4%)