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Endocrinology 04

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what peptide dec GH and other pituitary hormone secretion?
somatostatin
In women, how does PRL excess usually present?
as oligo or amenorrhea
Is PRL excess usually diagnosed earlier in men or women?
in women, as oligo or amenorrhea

men experience some dec libido, but may not seek help --> therefore are diagnosed later
can inc prolactin be caused by estrogen?
absolutely --> this occurs in new moms
how does primary hypothyroidism lead to PRL excess?
thyroid failure increases pro-TRH mRNA --> TRH is a PRL stimulator
how can a basal skull fracture lead to INC PRL?
basal skull fracture --> severed pituitary stalk --> dec inhibitory control by dopamine --> inc PRL
where is PRL broken down?
kidney

therefore, renal failure can cause inc PRL
is oral testosterone safe for men?
NO, use instead injections or patches/gels
how does GH cause growth of bones?
GH --> INC IGF-1 --> stimulates chondrocyte proliferation
bone age
look at wrist

anything that delays growth can delay bone age

precocious puberty (and maybe acromegaly) --> greater bone age
thyroid hormones are essential for normal postnatal growth and brain development. name two distinct growth-promoting actions.
(1) enhance pituitary GH secretion in response to GRH

(2) direct stimulatory effect on cartilage growth; act in concert with IGF's
outline the components of the adrenal gland
Cortex -- Secretes steroids

Outer-most zona glomerulosa

Intermediate fasciculata

Innermost Reticularis (clear cells) -- 80% of cortex

Dark compact cells--10% of cortex

Medulla -- secretes neuropeptides (Neural crest)
adrenal cortex: zona glomerulosa -- secretes what?
mineralocorticoids (aldosterone)
adrenal cortex: fasciculata and retiularis -- secrete what?
the two are a functional unit that secrete glucocorticoids and sex steroids
what is the main glucocorticoid secreted by the adrenal cortex?
cortisol
cortisol
Increases protein breakdown, nitrogen excretion, hepatic gluconeogenesis, extracellular fluid, appetite, fat deposition in the upper body, chance of infection

Decreases Leukocyte adhesion and diapedesis, inflammation, bacterial lysis in leukocytes, numbers of T-cells, and inhibits migration of water into cells
Aldosterone
Major regulator of extracellular fluid
Major regulator of potassium metabolism
Excess aldosterone results in sodium retention, loss of potassium, expansion of extracellular fluid compartment, and hypertension

Decreased aldosterone results in contraction of extracellular fluid and potassium retention
Testosterone
Accentuates male characteristics and suppresses female characteristics
Primary Addison's
due to adrenal insufficiency; should be suspected when there is marked skin pigmentation
Secondary Addison's
pituitary or hypothalamic insufficiency (no skin pigmentation)
Addison's clinical picture
Insidious, progressive weakness, fatigue, anorexia, nausea & vomiting, weight loss, hypotension, hyperpigmentation in skin and oral mucosa due to >ACTH and POMC precursor.

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normal pituitary

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Gross of a large chromophobe adenoma. Notice the location of the tumor in relation to the optic chiasm to explain visual field changes.

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Lateral view of a chromophobe adenoma.This radiograph offers a side view of the expanded sella (between the orbit on the left and the radio-dense mastoid on the right).

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Pituitary Chromophobe Adenoma

This is a low power view of the tumor. In it one sees the more compactly arranged area of adenoma composed of similar cells, a fibrous band produced by the pressure of the adenoma's growth (in the middle), and a more loosely organized fragment of residual normal pituitary composed of a variety of cells.

from left to right you've got

heterogenous (normal) --> capsule (fibrous tissue) --> artifact --> homogeneous adenoma (abnormal)

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Pituitary Chromophobe Adenoma

This photograph is a high power view of the adenoma itself.

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Craniopharyngioma of the Pituitary Gland

This photograph of a lateral X-ray of the skull shows the expansion of the sella turcica and calcification in mass (look between arrows).

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Craniopharyngioma of the Pituitary Gland

A sagittal section of the brain shows a large craniopharyngioma below the cerebral ventricle. Note the stippled pattern of the tumor.

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Craniopharyngioma of the Pituitary Gland

This low power view of a section of craniopharyngioma shows a cystic area on the left, in the zones to the center, and lower right epithelia producing acellular substance, and a loose mesenchyme filling the rest of the field.

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Craniopharyngioma of the Pituitary Gland

A mid power view shows precursor dental tissues to the right.

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Craniopharyngioma of the Pituitary Gland

Amorphous dental material is seen in these tumors.

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Infarction of the Pituitary

This is a cross-section of an old infarct of the pituitary showing infarct (yellow) surrounded by normal pituitary (brown). The infarcted zone shows yellow fibrillar appearance.

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Infarction of the Pituitary

This photograph contrasts the residual viable pituitary (on the right) with the infarcted necrotic area (on the left). Notice the ghost architecture and the acellular area of infarction in this case of Sheehan's
syndrome.

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Normal Adrenal & Cortical Adenoma of Adrenal Gland

Cross section of normal adrenal cortex and medulla.

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Normal Adrenal & Cortical Adenoma of Adrenal Gland

A higher power view of cortex shows three layers.

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Normal Adrenal & Cortical Adenoma of Adrenal Gland

Gross specimen of a cortical adenoma of the adrenal (round structure) attached to normal adrenal below.

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Normal Adrenal & Cortical Adenoma of Adrenal Gland

An adenoma made up of compact clear cells is seen on the left hand side, compressing residual, normal cortex on the right.

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Pheochromocytoma of Adrenal Gland

Large pheochromocytoma of adrenal with necrosis and hemorrhage.

Note the "mahogany" color

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Pheochromocytoma of Adrenal Gland

This high power field emphasizes the variety of sizes and shapes and nuclear pleomorphism of the cluster of cells that make up even a benign pheochromocytoma.

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Metastatic Small Cell Carcinoma of Adrenal Gland

Picture of gross specimen showing metastatic small cell carcinoma to the adrenal.

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Metastatic Small Cell Carcinoma of Adrenal Gland

This slide shows metastatic small cell carcinoma surrounding normal adrenal.

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Metastatic Small Cell Carcinoma of Adrenal Gland

Higher power view reveals the dark pleomorphic small cells of carcinoma of the lung.
what is the most common cause of hypothyroidism?
autoimmune thyroiditis (Hashimoto's disease)
name two "central" etiologies of hypothyroidism
(1) pituitary disease (TSH deficiency)

(2) hypothalamic disease (TRH deficiency)
what are three common causes of hypothyroidism?
(1) Hashimoto's autoimmune thyroiditis

(2) After treatment for hyperthyroidism

(3) Iodine deficiency (not in US)
disorders associated with inc incidence of hypothyroidism?
(1) Addison's disease

(2) Pernicious anemia

(3) Type I DM

(4) Autoimmune polyendocrine deficiency syndrome

(5) Scleroderma, rheumatoid arthritis

(6) celiac disease, primary biliar cirrhosis

(7) Klinefelter's, Turner's, and Down's Syndrome
myxedema
clinical manifestation of hypothyroidism found only in more severe cases

accumulation of hydrophilic mucopolysaccharides in subcutaneous tissues, which is responsible for facial puffiness and "swelling" in peripheral tissues
what is the single most sensitive test for the diagnosis of primary hypothyroidism?
serum TSH determination
subclinical hypothyroidism
elevated serum TSH with free T4 concentrations within the normal range

Note that many of these patients WILL have clinical manifestations
what is the appropriate therapy for hypothyroidism in the overwhelming majority of patients?
levothyroxine (T4)
name four available forms of thyroid hormone replacement?
(1) l-thyroxine (T4)

(2) l-triiodothyronine (T3)

(3) animal thyroid extracts -- Armour Thyroid

(4) T4/T3 combinations (Thyrolar, Euthroid)
pregnancy -- dose of thyroxine needed to maintaing euthyroid state
dose needed may inc by as much as 25-50%
cretinism
hypothyroidism occuring in the newborn period; mental retardation, short stature, and a characteristic puffiness of the face and hands

treatment with thyroid hormone before three months of age can result in normal intellectual development in 85% of cases
juvenile (childhood) hypothyroidism
hypothyroidism occurring after age three

rarely associated with permanent mental retardation; intellectual slowing and delayed skeletal maturation are characteristic findings, with other features being similar to those seen in adults
myxedema coma
end stage of untreated hypothyroidism

progressive weakness, altered mental status, hypothermia, hypoventilation, hypotension, hypoglycemia, and hyponatremia
is acute thyroiditis common?
no, it is rare
Acute Thyroiditis
- agents
- clinical manifestations
- lab
- diagnosis
- treatment
- course
- agents: bacteria (staph, strep), fungi

- clinical manifestations: fever, sweats, tachycardia, pain and tenderness in lower anterior neck, local erythema and warmth

- lab: leukocytosis, normal TSTs

- diagnosis: clinical, needle aspiration for culture

- treatment: parenteral antibiotics, abcess drainage

- course: complete resolution with normal TSTs
is subacute granulamatous (de Quervain's) Thyroiditis common?
not uncommon
Subacute Thyroiditis
- etiology
- clinical features
- lab
- diagnosis
- treatment
- clinical course
- etiology: probably viral

- clinical features: anterior neck pain radiating to ears, malaise, fever; thyroid moderately enlarged, tender, often asymmetric

- lab: normal WBC, elevated sed rate, 50% have elevated TSTs, dec RAI uptake

- diagnosis: clinical, sed rate, TST's, RAIU

- treatment: ASA, prednisone in severe cases, beta-blockers for hyperthyroidism

- clinical course: 2-6 months, with occasional recurrences
what is the main thing to remember about clinical presentation of subacute lymphocytic thyroiditis?
Subacute Lymphocytic ("Painless") Thyroiditis

- the thyroid is moderately enlarged, firm, and NON-TENDER
is Invasive Fibrous (Riedel's) Thyroiditis common?
NO, it's very rare
Invasive Fibrous (Riedel's) Thyroiditis
- clinical
- treatment
clinical: presents as stony hard, nontender mass, fixed to surrounding structures; may cause tracheal narrowing

treatment: surgery, corticosteroids, tamoxifen
Is Chronic Lymphocytic (Hashimoto's, Autoimmune) Thyroiditis common?
YES
Chronic Lymphocytic Thyroiditis
- clinical
- lab
- diagnosis
- treatment
- course
- clinical: firm diffuse goiter with or without hypothyroidism; goiter may be nodular, asymmetric, and occasionally there is no goiter

- lab: patient is usually normal or hypothyroid; serum positive for anti-thyroglobulin and anti-thyroid peroxidase (TPO) antibodies; scan -- patchy, non-homogeneous uptake

- diagnosis: anti-thyroid antibodies (TPO); occasionally fine needle biopsy

- treatment: thyroxine for hypothyroidism and goiter suppression; rarely, surgery for large goiters

- course: progression to hypothyroidism in most patients
toxic goiter
hyperthyroid
nontoxic goiter
euthyroid or hypothyroid
endemic goiter
goiter occurring in a region where goiter is prevalent
what is the treatment for goiter with hypothyroidism?
thyroid hormone (L-thyroxine)
T/F Thyroid nodules are common, thyroid cancer is uncommon, and death from thyroid cancer is rare.
T
diurnal rhythm of ACTH
diurnal rhythm resulting in changes in amplitude but not frequency

peak ACTH pulsatility 3-5 hours after onset of sleep and persists through the first hour after awakening

serum cortisol therfore peaks between 6-8 AM and wanes as the day progresses

this circadian rhythm is also synchronized with dark-light shifts
how does stress effect cortisol levels?
both physical (e.g. surgery, infection) and psychological stress result in the hypothalamic release of CRH (and ADH), thus cortisol levels are expected to be high, and diurnal variation is lost (chronic elevation)
cortisol actions (5)
(1) maintain contractility of heart

(2) modulate vascular response to Beta-agonists (inc receptors, dec inactiv of catechol)

(3) antagonize action of insulin (stim gluconeo, catabolic effect)

(4) inc GFR

(5) immunosuppressive and anti-inflammatory effects such as inhibition of antibody and cytokine production, dec white cell migration and activity
renin
secreted by JG apparatus of kidney in response to:

(1) dec intravascular volume

(2) dec serum [Na+]

(3) inc serum [K+]

(4) dec BP

(5) prostaglandins

(6) beta-adrenergic stimulation
first action of renin
cleavage of angiotensinogen (secreted by liver) to angiotensin I
where is Angiotensin I cleaved to Angiotensin II?
by ACE in the lungs
In what two ways does Angiotensin II inc BP?
direct: vasopression

indirect: stimulates synth and secretion of aldosterone by ZG --> sodium retention by the kidney
Primary AI
destruction of adrenal cortex resulting in both glucocorticoid and mineralocorticoid deficiency
Secondary AI
defect is at level of pituitary, or rarely, the hypothalamus, leading to adrenal atrophy due to loss of normal trophic stimulation by ACTH

**** Secondary adrenal insufficiency results in primarily glucocorticoid and not mineralocorticoid deficiency
In autoimmune primary adrenal insufficiency, what is usually occurring?
antibodies to 21-hydroxylase
what is a common fungal cause of primary adrenal deficiency?
histoplasmosis
name four drugs that can cause primary adrenal deficiency
(1) Ketoconazole -- antifungal agent which blocks cytochrome P-450's (including those responsible for the synth of cortisol)

(2) Metyrapone -- 11-Beta-hydroxylase

(3) Aminoglutethimide -- inhibits side-chain cleavage enzyme

(4) O, p'-DDD (mitotane)
adrenoleukodystrophy
X-linked recessive disorder resulting in progressive demyelination of the CNS
what is the most common cause of secondary adrenal insufficiency?
pituitary axis suppression by exogenous glucocorticoids
what are the symptoms and signs of Chronic Primary AI?
Symptoms -- weakness and fatigue, anorexia, nausea/abdominal pain, vomiting

Signs -- weight loss, hyperpigmentation, hypotension, vitiligo
what lab findings are associated with chronic primary AI?
(1) hyponatremia

(2) hyperkalemia

(3) anemia, lymphocytosis, eosinophilia

(4) hypoglycemia
how are the symptoms/signs of secondary AI different from primary AI?
in secondary AI:

- greater incidence of headache
- hyperpigmentation absent
- no hyperkalemia due to preserved mineralocorticoid secretion from the ZG, but hyponatremia may still be present due to INC ADH levels in response to the DEC intravascular volume
metyrapone
inhibits the final (11-Beta-hydroxylase) step in cortisol synthesis
what is the gold standard test for secondary AI?
insulin-induced hypoglycemia
treatment of chronic primary AI
(1) maintenance glucocorticoids (hydrocortisone or cortisone acetate)

(2) oral mineralocorticoid (e.g. fludrocortisone)

(3) instruct to inc glucocorticoid dose in stress (fever, surgery, etc)

(4) ID bracelet
treatment of chronic secondary AI
same as for primary except without the mineralocorticoid
what are the three most common cases where you'd see acute AI (adrenal crisis)
(1) stress in a patient with pre-existing subclinical AI

(2) rapid withdrawal of glucocorticoids in a patient treated chronically with glucocorticoids

(3) Waterhouse-Friderichsen syndrome (meningococcal sepsis leading to DIC with resulting adrenal hemorrhage)
treatment for acute AI (adrenal crisis)
(1) establish IV access and infuse saline and glucose

(2) draw blood for plasma cortisol, ACTH, electrolytes, and glucose

(3) high dose hydrocortisone (100 mg IV q 6-8 hrs) has both glucocorticoid as well as mineralocorticoid effects or can use dexamethasone 4 mg every 12 hours
Cushing's syndrome
glucocorticoid excess of any etiology
Cushing's disease
pituitary ACTH excess leading to adrenal stimulation and glucocorticoid excess
five main metabolic consequences of excessive glucocorticoid activity
(1) IGT to frank DM

(2) adiposity

(3) protein wasting

(4) immunosuppression

(5) psychological disturbances

"Im A PImP"
Overnight high dose dexamethasone suppression test
(1) measure cortisol at 8 AM

(2) 8 mg dexamethasone at 11 PM, measure cortisol net day at 8 AM

(3) suppression of cortisol level to less than 68% of baseline cortisol is consistent with pituitary disease

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