11 - Endocrine - 2021 Edition Endpoints

USMLE ENDPOINT ENDOCRINE
ENDOCRINE EMBRYOLOGY
Thyroid development:
 Thyroid diverticulum arises from floor of
primitive pharynx and descends into neck.
 Connected to tongue by thyroglossal duct,
which normally disappears but may
persist as cysts or the pyramidal lobe of
thyroid.
 Foramen cecum is normal remnant of
thyroglossal duct.
 Most common ectopic thyroid tissue site
is the tongue (lingual thyroid).
 UW: Failure of migration of the thyroid
gland can cause a lingual thyroid.
Surgeons should be careful when
removing any mass along the thyroglossal
duct s usual path, as the mass could be the
only thyroid tissue present in a patient.
Removal may result in hypothyroidism if
it is the only thyroid tissue present.
 Thyroglossal duct cyst presents as an
anterior midline neck mass that moves with swallowing or protrusion of the tongue
(vs. persistent cervical sinus leading to branchial cleft cyst in lateral neck).
 Thyroid tissue and parafollicular cells (aka, C cells, produce Calcitonin) of the
thyroid are derived from endoderm.
 UW: Formation of the mature thyroid occurs when thyroid follicles (from an
evagination of the pharyngeal epithelium) and parafollicular C-cells (originating
in ultimobranchial bodies) fuse together.
1 Page Dr Ahmed Shebl
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ENDOCRINE ANATOMY
Adrenal cortex and medulla:

Adrenal cortex (derived from mesoderm) and medulla (derived from neural crest).
 GFR corresponds with Salt (mineralocorticoids), Sugar (glucocorticoids), and Sex
(androgens). “The deeper you go, the sweeter it gets.”
 UW: Chromaffin cells:
1) Modified postganglionic sympathetic neurons.
2) Derived from the neural crest.
3) Receive sympathetic input (neuroendocrine cells).
4) They are stimulated by acetylcholine released by sympathetic
preganglionic neurons.
5) Secrete catecholamines (80% epinephrine. 20% norepinephrine)
directly into the bloodstream to amplify sympathetic nervous system
activity.
Pituitary gland:
Anterior pituitary (adenohypophysis):
 Secretes FSH, LH, ACTH, TSH, prolactin, GH.
 Melanotropin (MSH) secreted from intermediate
lobe of pituitary.
 Derived from an out-pouching of the pharyngeal
roof and is called Rathke's pouch.
1) UW: Craniopharyngioma are tumors
arising from Rathke's pouch remnants
in the anterior pituitary.
a) They characteristically have
three components: solid, cystic,
and calcified.
b) They present during childhood,
usually, with mass effect and visual deficits.
2) α subunit—hormone subunit common to TSH, LH, FSH, and hCG.
3) β subunit—determines hormone specificity.
4) ACTH and MSH are derivatives of proopiomelanocortin (POMC).
a) UW: Proopiomelanocortin (POMC) is pentapeptide released
on response to noxious stimuli which is then cleaved into 3
components (B-endorphin & ACTH & MSH). ―There may be a
close physiological relationship between the stress axis and the
opioid system‖
5) Basophils (B-FLAT): —FSH, LH, ACTH, TSH. Acidophils: GH,
PRL.
 Posterior pituitary (neurohypophysis):
1) Stores and releases vasopressin (antidiuretic hormone, or ADH) and
oxytocin.
2) Both made in the hypothalamus (supraoptic and paraventricular nuclei)
and transported to posterior pituitary via neurophysins (carrier
proteins).
3) Derived from neuroectoderm (extension of the hypothalamic neurons)
4) UW: ADH is synthesized in the paraventricular and supraoptic nuclei
of the hypothalamus. After synthesis, ADH is transported to the
posterior pituitary for storage and later release into the circulation.
a) Injury to the posterior pituitary or infundibulum:
 Can cause transient Dl.
 But if the hypothalamic nuclei are intact, axonal
regeneration and hypertrophy will allow adequate ADH
release into the circulation.
b) By contrast, loss of vasopressinergic neurons in the
hypothalamic nuclei due to trauma, surgery, or infiltrative
disease (eg, histiocytosis X) will lead to permanent Dl.
5) UW: Neurophysins are carrier proteins for oxytocin and vasopressin

(ADH). Oxytocin and vasopressin are carried by unique neurophysins
from their site of production in the cell bodies of the paraventricular
and supraoptic nuclei to their site of release in the axon terminals of
the posterior pituitary. Point mutations in neurophysin II underlie
most cases of hereditary hypothalamic diabetes insipidus, a disorder
resulting from insufficient ADH release into the systemic circulation.
Endocrine pancreas:
 Islets of Langerhans are collections of α, β, and δ endocrine cells.
 Islets arise from pancreatic buds.
ƒ α = glucagon (peripheral)
ƒ β = insulin (central)
ƒ δ = somatostatin (interspersed)
 Insulin (β cells) inside.
Thyroid gland anatomy:

Blood supply of the thyroid: The superior thyroid artery (a branch of the external
carotid artery) and the inferior thyroid artery (a branch of the thyrocervical trunk).
The superior thyroid artery and vein and external branch of the superior laryngeal
nerve course together in a neurovascular triad that originates superior to the thyroid
gland and lateral to the thyroid cartilage.
The external branch is at risk of injury during thyroidectomy as it courses just deep to
the superior thyroid artery. The cricothyroid muscle is the only muscle innervated by
this nerve. The cricothyroid muscle acts to tense the vocal cords, and denervation
injury may cause a low, hoarse voice with limited range of pitch.
The internal branch of the superior laryngeal nerve does not innervate any muscles
but provides sensory innervation to the laryngeal mucosa above the vocal folds.
The inferior thyroid artery is in close relation to left recurrent laryngeal nerve.
UW: Nerve supply of the larynx:

 All muscles of the larynx are supplied by RLN EXCEPT cricothyroid (by external
branch of the superior laryngeal nerve).
 Mucosa above epiglottis  external branch of the superior laryngeal nerve.
 Mucosa below epiglottis  RLN.
ENDOCRINE PHYSIOLOGY
Insulin:
SYNTHESIS:
 Preproinsulin (synthesized in RER)  cleavage of ―presignal‖  proinsulin
(stored in secretory granules)  cleavage of proinsulin  exocytosis of insulin
and C-Peptide equally.
1) UW: Cleavage of proinsulin in the islet cell secretory granules yields
insulin and C-peptide, which are stored in the granule until they are
secreted in equimolar amounts.
 Insulin and C-peptide are ↑ in insulinoma and sulfonylurea use, whereas
exogenous insulin lacks C-peptide.
 UW: Sulfonylurea or meglitinide abuse and insulinoma cause increased insulin,
c-peptide, and pro-insulin levels. The only way to distinguish between insulinoma
and sulfonylurea or meglitinide abuse is by screening the urine or blood for
hypoglycemic agents.
SOURCE:
 Released from pancreatic β cells.
FUNCTION:
 Binds insulin receptors (tyrosine kinase activity (1)), inducing glucose uptake
(carrier mediated transport) into insulin-dependent tissue (2) and gene
transcription.
 Anabolic effects of insulin:
1) ↑glucose transport in skeletal muscle and adipose tissue
2) ↑ glycogen synthesis and storage
3) ↑ Triglyceride synthesis
4) ↑ Na+ retention (kidneys)
5) ↑ protein synthesis (muscles)
6) ↑ cellular uptake of K+ and amino acids
7) ↓ glucagon release
8) ↓ Lipolysis in adipose tissue.
 Unlike glucose, insulin does not cross placenta.
Transport of glucose
 Into the cells of most tissues occurs by means of facilitated diffusion.
 Glucose moves from areas of high concentration to areas of low concentration
with the help of transmembrane glucose transporter proteins (GLUT).
 These carrier proteins are stereoselective and have preference for D-glucose.
 Insulin-dependent glucose transporters:
1) GLUT4: adipose tissue, striated muscle (exercise can also increase
GLUT4 expression).
 Insulin-independent transporters:
1) GLUT1: RBCs, brain, cornea, placenta
2) GLUT2 (bidirectional): β islet cells, liver, kidney, small intestine
3) GLUT3: brain, placenta
4) GLUT5 (fructose): spermatocytes, GI tract
 Brain utilizes glucose for metabolism normally and ketone bodies during
starvation.
 RBCs utilize glucose because they lack mitochondria for aerobic metabolism.
BRICK L (insulin-independent glucose uptake):
Brain, RBCs, Intestine, Cornea, Kidney, Liver.
 UW: In normal individuals, overt hypoglycemia does not occur with exercise
because a drop in blood glucose will stop insulin release from the beta cells and
counter-regulatory hormones (eg, glucagon) will increase endogenous glucose
production via glycogenolysis and gluconeogenesis. However, patients taking
exogenous insulin are vulnerable to exercise-induced hypoglycemia as insulin
will continue to be released from the injection site despite falling glucose levels. In
addition, strenuous exercise may cause changes in skin perfusion that can lead to
increased insulin absorption (especially if the insulin is injected into an exercising
limb rather than the abdominal area).
REGULATION
1) Glucose is the major regulator of insulin release.
2) ↑ Insulin response with oral vs IV glucose because of incretins such as glucagon-like
peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), which
are released after meals and ↑ β cell sensitivity to glucose.
3) Release ↓ by α2, ↑ by β2.
a) KQB: Clonidine (alpha-2 agonist) inhibits insulin secretion.
UW: Alpha-2 adrenergic receptors inhibit insulin secretion, and beta-2 adrenergic
receptors stimulate insulin secretion. The alpha-2-mediated inhibitory effect is
generally predominant, causing sympathetic stimulation to lead to overall inhibition
of insulin secretion.
SECRETION:
 Glucose enters β cells  ↑ ATP generated from glucose metabolism closes K+
channels (target of sulfonylureas) and depolarizes β cell membrane.
 Voltage-gated Ca2+ channels open  Ca2+ influx and stimulation of insulin
exocytosis.
 UW: Mutations in Pancreatic ATP sensitive potassium channel:

a) Neonatal DM: caused by mutations of the K (ATP) channels in which elevated
glucose levels do not lead to appropriate depolarization and insulin release.
These patients can be treated successfully with sulfonylureas which bind to K
(ATP) channels and cause closure independent of ATP.
b) Conversely, a mutation causing an increased affinity for ATP and inappropriate
closure of the channels would lead to excessive insulin release and frequent
hypoglycemia.
 UW: Causes of insulin resistance:

1) ↑TG & FFA  lipotoxicity  insulin resistance & ↓insulin secretion.
a) NB: Lowering FFA improves B-cell function and insulin
resistance.
2) Serine phosphorylation of B-subunit of the receptor  ↓downstream
signaling (as tyrosine kinase action will ↓)
a) This action is induced by (TNF-alpha & glucagon &
glucocorticoids) by serine kinase.
3) ↑waist-to-hip ratio  ↑insulin resistance. Waist  indicate visceral
fat  much stronger correlation with insulin resistance.
4) Human placental lactogen:
 UW: Acanthosis nigricans is one of the signs of insulin resistance.

a) Insulin resistance in adipose cells hinders the antilipolytic effects of insulin,
leading to lipolysis and high plasma free fatty acid levels.
b) Chronically elevated free fatty acid levels contribute to insulin resistance by
impairing insulin-dependent glucose uptake in liver and muscle.
c) They also increase hepatic gluconeogenesis and insulin secretion and stimulate
release of proinflammatory cytokines.
d) Other factors that contribute to insulin resistance include obesity and a sedentary
lifestyle.
 UW: Visceral obesity as measured by waist circumference or waist-to-hip ratio is an
important predictor of insulin resistance.
Glucagon
SOURCE: Made by α cells of pancreas.
FUNCTION: Glycogenolysis, gluconeogenesis, lipolysis, ketone production.
REGULATION: Secreted in response to hypoglycemia. Inhibited by insulin,
hyperglycemia, and somatostatin.
UW: Glucagon ↑glucose from the liver. Unlike epinephrine, glucagon has insignificant
effect on skeletal muscles & adipocytes.
Prolactin:
SOURCE:
 Secreted mainly by anterior pituitary. Structurally homologous to growth hormone.
FUNCTION:
 Stimulates milk production in breast.
 Inhibits ovulation in females and spermatogenesis in males by inhibiting GnRH
synthesis and release.
 Excessive amounts of prolactin associated with ↓ libido.
REGULATION:
 Prolactin secretion from anterior pituitary is tonically inhibited by dopamine from
tuberoinfundibular pathway of hypothalamus.
1) Dopamine agonists (eg, bromocriptine) inhibit prolactin secretion and
can be used in treatment of prolactinoma.
2) Dopamine antagonists (eg, most antipsychotics) and estrogens (eg,
OCPs, pregnancy) stimulate prolactin secretion.
 Prolactin in turn inhibits its own secretion by ↑ dopamine synthesis and secretion
from hypothalamus.
UW: ↑Prolactin  ↑risk of bone fracture. AS ↑prolactin  ↓GnRH  ↓estrogen 

accelerated bone loss exactly as postmenopausal osteoporosis.
 TRH ↑prolactin secretion (eg, in 1° or 2° hypothyroidism).
Growth hormone (somatotropin):

 SOURCE Secreted by anterior pituitary.
 FUNCTION:
1) Stimulates linear growth and muscle mass through IGF-1 (somatomedin C)
secretion by liver.
2) ↑ Insulin resistance (diabetogenic).
Somatostatin keeps your growth static.
Somatomedin mediates your growth.
 REGULATION:
1) Released in pulses in response to growth hormone–releasing hormone (GHRH).
 UW: The cyclic rhythm of GH is related more to sleep cycle rather than
circadian rhythm.
 In Delta wave sleep  ↑ GH & prolactin.
 The circadian rhythm control the release of the ACTH not the
GH.
 The circadian rhythm is controlled by the suprachiasmatic nucleus
in the hypothalamus.
2) Secretion ↑ during exercise, deep sleep, puberty, hypoglycemia.
3) Secretion inhibited by glucose and somatostatin release via negative feedback by
somatomedin.
4) Excess secretion of GH (eg, pituitary adenoma) may cause acromegaly (adults) or
gigantism (children). Treat with somatostatin analogs (eg, octreotide) or surgery.
Appetite regulation:
Ghrelin:
 Stimulates hunger (orexigenic effect) and GH release (via GH secretagog
receptor).
 Produced by stomach.
 Sleep deprivation or Prader-Willi syndrome  ↑ ghrelin production.
Ghrelin makes you hunghre.
Leptin:
 Satiety hormone.
 Produced by adipose tissue.
 Mutation of leptin gene  congenital obesity.
 Sleep deprivation or starvation  ↓ leptin production.
Leptin keeps you thin.
Leptin decreases food intake in the following important ways:

1. Leptin decreases the production of neuropeptide Y; a potent appetite stimulant, in the
arcuate nucleus of the hypothalamus.
2. Leptin stimulates the production of proopiomelanocortin (POMC) in the arcuate nucleus.
Alpha-melanocyte-stimulating hormone (alpha-MSH) is produced by cleavage of POMC and
inhibits food intake.
―Sustained elevation in leptin levels from the
enlarged fat stores results in leptin desensitization‖
Endocannabinoids:
1) Act at cannabinoid receptors in hypothalamus and nucleus
accumbens, two key brain areas for the homeostatic and hedonic
control of food intake  ↑appetite.
2) Exogenous cannabinoids cause “the munchies.”
Antidiuretic hormone
SOURCE: Synthesized in hypothalamus (supraoptic nuclei), stored and secreted by
posterior pituitary.
FUNCTION:
 Regulates serum osmolarity (V2-receptors) and blood pressure (V1-
receptors).
 Primary function is serum osmolarity regulation (ADH ↓ serum osmolarity, ↑
urine osmolarity) via regulation of aquaporin channel insertion in principal
cells of renal collecting duct.
 ADH level is ↓ in central diabetes insipidus (DI), normal or ↑ in
nephrogenic DI.
 Nephrogenic DI can be caused by mutation in V2-receptor.
 Desmopressin acetate (ADH analog) is a treatment for central DI and
nocturnal enuresis.
REGULATION:
 Osmoreceptors in hypothalamus (1°); hypovolemia.
UW: Damage to the posterior pituitary gland produces only transient central Dl,
whereas damage to the hypothalamic nuclei will cause permanent central Dl.
Adrenal steroids and congenital adrenal hyperplasia:
UW: Treatment of congenital adrenal hyperplasia involves low doses of exogenous

corticosteroids to suppress excessive ACTH secretion and reduce stimulation of the adrenal
cortex.
UW: 5-α reductase deficiency:
 There are 2 types of 5a-reductase:

o Type 1 is present in postpubescent skin.
o Type 2 is found predominantly in the genitals.
 Deficiency of 5a-reductase type 2 results in diminished conversion of testosterone to
DHT in the male urogenital tract.
o In the male fetus with this genetic defect, the internal genitalia develop
normally under the influence of testosterone, but the external genitalia do not
develop properly due to the lack of DHT, resulting in male
pseudohermaphroditism. The genitalia at birth can range from a small phallus
with hypospadias to ambiguous or female-type genitalia. Such children are
often raised as females until they reach puberty, when high levels of
testosterone and the action of 5a-reductase type 1 result in masculinization
with male-pattern muscle mass, voice deepening, penile and scrotal growth,
and testicular descent.
Cortisol:
 SOURCE Adrenal zona fasciculata. Bound to corticosteroid-binding globulin.
 FUNCTION:
1) ↑ Appetite
2) ↑ Blood pressure.
3) Upregulates α1-receptors on arterioles  ↑ sensitivity to norepinephrine and
epinephrine (permissive action).
4) At high concentrations, can bind to mineralocorticoid (aldosterone) receptors.
5) ↑ Insulin resistance (diabetogenic)
6) ↑ Gluconeogenesis, lipolysis, and proteolysis (↓ glucose utilization)
7) ↓ Fibroblast activity (poor wound healing, ↓ collagen synthesis, ↑ striae).
8) ↓ Inflammatory and Immune responses:
a) Inhibits production of leukotrienes and prostaglandins.
b) Inhibits WBC adhesion  neutrophilia
c) Blocks histamine release from mast cells
d) Eosinopenia, lymphopenia
e) Blocks IL-2 production
9) ↓ Bone formation (↓ osteoblast activity).
 UW: Glucocorticoids are predominantly catabolic, causing muscle weakness, skin
thinning, impaired wound-healing, osteoporosis, and immunosuppression. However,
they increase liver protein synthesis, specifically the enzymes involved in
gluconeogenesis and glycogenesis. This, along with peripheral antagonism of the effects
of insulin, contributes to the development of hyperglycemia.
 Exogenous corticosteroids can cause reactivation of TB and candidiasis (blocks IL-2
production).
 REGULATION:
1) CRH (hypothalamus) stimulates ACTH release (pituitary)  cortisol production
in adrenal zona fasciculata.
2) Excess cortisol ↓ CRH, ACTH, and cortisol secretion.
3) Chronic stress induces prolonged secretion.
 UW: Acute effects of corticosteroid therapy:
1) Increased neutrophils (lack of margination)
2) All other cell counts decreased
 UW: Maternal and fetal cortisol both help to accelerate fetal lung maturation by
stimulating surfactant production and can be assessed through various biochemical tests
during amniocentesis (L/S ratio). Corticosteroids are administered to pregnant mothers
who are at risk of having a premature delivery with fetal lung immaturity.
 UW: High doses of corticosteroid therapy can sometimes cause corticosteroid-induced

psychosis (confusion, hallucinations), hypoalbuminemia is a risk factor, and the
neuropsychiatric symptoms typically resolve with discontinuation of therapy.
Calcium homeostasis:
Plasma Ca2+ exists in three forms:
 Ionized/free (~ 45%, active form)
 Bound to albumin (∼ 40%)
 Bound to anions (∼ 15%)
↑ in pH  ↑ affinity of albumin (↑ negative charge) to bind Ca2+  hypocalcaemia
(cramps, pain, paresthesias, carpopedal spasm).
Ionized/free Ca2+ is 1° regulator of PTH; changes in pH alter PTH secretion,
whereas changes in albumin do not.
Vitamin D
SOURCE
 D3 from exposure of skin to sun, ingestion of fish and plants.
 D2 from ingestion of plants, fungi, yeasts.
 Both converted to 25-OH in liver and to 1,25-(OH)2 vitamin D (active form)
in kidney.
 UW: Activated macrophages in sarcoidosis and other granulomatous diseases
produce excess 1,25- dihydroxyvitamin D. which can cause hypercalcemia by
increasing intestinal absorption of calcium and phosphate.
 24, 25-(OH)2 D3 is an inactive form of vitamin D.

1) UW: 25-hydroxyvitamin D can also be converted to 24,25-
dihydroxyvitamin D (an inactive form) by 24-hydroxylase in the
kidneys.
2) This is primarily driven by elevated calcium levels (and the resulting
lower PTH levels) and is not affected by sunlight.
FUNCTION
 ↑ Absorption of dietary Ca2+ and PO43-.
 Enhances bone mineralization.
 PTH leads to ↑ Ca2+ reabsorption and ↓ PO4- reabsorption in the kidney,
whereas 1,25-(OH)2 D3 leads to ↑ absorption of both Ca2+ and PO4- in the
gut.
REGULATION:
 ↑ PTH, ↓ Ca2+, ↓ PO43-  ↑ 1,25-(OH)2 production.
 1,25-(OH)2 feedback inhibits its own production.
Deficiency:
 Rickets in kids, osteomalacia in adults.
 Caused by malabsorption, ↓ sunlight, poor diet, and chronic kidney failure.
Parathyroid hormone:
SOURCE: Chief cells of parathyroid.
FUNCTION:
 ↑ Bone resorption of Ca2+ and PO43-.
 ↑ Kidney reabsorption of Ca2+ in distal convoluted tubule.
 ↓ Reabsorption of PO43- in proximal convoluted tubule.
 ↑ 1,25-(OH)2 D3 (calcitriol) production by stimulating kidney 1α-hydroxylase
in proximal convoluted tubule.
 PTH ↑ serum Ca2+, ↓ serum (PO43–), ↑ urine (PO43-), ↑ urine cAMP.
 ↑ RANK-L (receptor activator of NF-κB ligand) secreted by osteoblasts and
osteocytes. Binds RANK (receptor) on osteoclasts and their precursors to
stimulate osteoclasts and ↑ Ca2+  bone resorption. (The PTH ↑osteoclastic
activity INDIRECTLY by increasing osteoblastic activity which activates
osteoclasts).
 Intermittent PTH release can also stimulate bone formation.
 PTH = Phosphate-Trashing Hormone.
 PTH-related peptide (PTHrP) functions like PTH and is commonly
increased in malignancies (eg, squamous cell carcinoma of the lung, renal cell
carcinoma).
 UW: Osteoprotegerin (OPG) is a physiologic decoy receptor that decreases

binding of RANK-L to RANK. Inhibition of RANK-L to RANK receptor
interaction reduces the differentiation and survival of osteoclasts, resulting in
decreased bone resorption and increased bone density.
 REGULATION
1) ↓ Serum Ca2+  ↑ PTH secretion.
2) ↑ Serum PO4-  ↑ PTH secretion.
3) ↓ Serum Mg2+  ↑ PTH secretion.
4) ↓↓ Serum Mg2+  ↓ PTH secretion.
Common causes of ↓ Mg2+ include diarrhea, aminoglycosides,
diuretics, alcohol abuse.
 UW: In chronic kidney disease, conversion of 25-hydroxyvitamin D to 1,25-

dihydroxyvitamin D in the kidneys is impaired. In addition, failure of glomerular and
tubular function results in phosphate retention and hypocalcemia. This leads to a
compensatory rise in parathyroid hormone (secondary hyperparathyroidism).
Calcitonin
SOURCE Parafollicular cells (C cells) of thyroid.
FUNCTION:
 ↓ Bone resorption of Ca2+.
 Calcitonin opposes actions of PTH.
 Not important in normal Ca2+ homeostasis.
 Calcitonin tones down serum Ca2+ levels and keeps it in bones.
REGULATION: ↑serum Ca2+  calcitonin secretion.
Thyroid hormones (T3/T4)

Iodine-containing hormones that control the body’s
metabolic rate.
SOURCE:
 Follicles of thyroid.
FUNCTION:
 Bone growth (synergism with GH). KQB:
Thyroid hormone is required for normal
synthesis and secretion of GH (thyroid
hormone is permissive for GH activity).
 CNS maturation
 ↑ β1 receptors in heart = ↑ CO, HR, SV,
contractility
 ↑ basal metabolic rate via ↑ Na+/K+-ATPase
activity  ↑ O2 consumption, RR, body
temperature.
 ↑ Glycogenolysis, gluconeogenesis, lipolysis.
REGULATION:
 TRH (hypothalamus) stimulates TSH
(pituitary), which stimulates follicular cells.
 May also be stimulated by thyroid-stimulating immunoglobulin (TSI) in
Graves’ disease.
 Negative feedback primarily by free T3/T4 to anterior pituitary (↓ sensitivity
to TRH) and hypothalamus (↓ TRH secretion).
 Wolff-Chaikoff effect—excess serum iodine temporarily inhibits thyroid
peroxidase  ↓iodine organifcation  ↓ T3/T4 production.
 Thyroxine-binding globulin (TBG) binds most T3/T4 in blood; only free

hormone is active.
 ↓ TBG in hepatic failure, steroids; ↑ TBG in pregnancy or OCP use (estrogen
↑TBG).
 T4 is major thyroid product; converted to T3 in peripheral tissue by 5′-
deiodinase.
 T3 binds nuclear receptor with greater affinity than T4.
 Thyroid peroxidase is the enzyme responsible for oxidation and
organifcation of iodide as well as coupling of monoiodotyrosine (MIT) and
di-iodotyrosine (DIT).
1) UW: Antibodies against thyroid peroxidase are present in more than
90% of patients with autoimmune (Hashimoto's) thyroiditis.
 DIT + DIT = T4.
DIT + MIT = T3.
 Propylthiouracil (PTU) inhibits both thyroid peroxidase and 5′-deiodinase.
Methimazole inhibits thyroid peroxidase only.
 Glucocorticoids inhibit peripheral conversion of T4 to T3.
 UW: Thyroid hormone exists in 3 forms:

1) T4 (thyroxine) is produced only in the thyroid and is the major
secretory product of the gland.
2) T3 (triiodothyronine) is the most active form of thyroid hormone;
although a small amount is produced by the thyroid gland, the majority
arises from peripheral deiodination of T4.
3) Reverse T3 (rT3) is an inactive form of thyroid hormone that is
generated almost entirely from peripheral conversion of T4.
 synthetic T3 (liothyronine) is not typically used for treating hypothyroidism
as its short half-life requires multiple daily dosing due to wide fluctuations in
plasma T3 levels.
Signaling pathways of endocrine hormones:
Signaling pathway of steroid hormones:
 Steroid hormones are lipophilic and therefore must circulate bound to specific
binding globulins, which ↑ their solubility.
 SHBG binds more avidly to testosterone more than estrogen.
 In men, ↑ sex hormone–binding globulin (SHBG) lowers free testosterone 
gynecomastia.
 In women, ↓ SHBG raises free testosterone  hirsutism.
 OCPs, pregnancy  ↑ SHBG.
 UW: Calcium-sensing receptors (CaSR) are transmembrane G-protein-coupled

(metabotropic) receptors that help to regulate the secretion of parathyroid hormone
(PTH) in response to changes in circulating calcium levels. Binding of calcium to
CaSR leads to inhibition of PTH release, whereas low calcium levels lead to increased
PTH release.
ENDOCRINE PATHOLOGY
Cushing syndrome:
ETIOLOGY:
 ↑ Cortisol due to a variety of causes:
 Exogenous corticosteroids: result in ↓ ACTH, bilateral adrenal atrophy. Most
common cause.
 Primary adrenal adenoma, hyperplasia, or carcinoma: result in ↓ ACTH,
atrophy of uninvolved adrenal gland. Can also present with
pseudohyperaldosteronism.
 ACTH-secreting pituitary adenoma (Cushing disease); paraneoplastic
ACTH secretion (eg, small cell lung cancer, bronchial carcinoids): result in ↑
ACTH, bilateral adrenal hyperplasia.
 Cushing disease is responsible for the majority of endogenous cases of
Cushing syndrome.
 UW: ACTH is the major trophic hormone of the zona fasciculata and
reticularis whereas the zona glomerulosa is primarily regulated by
angiotensin II. Prolonged ACTH stimulation causes hyperplasia (not
hypertrophy) of the zona fasciculata and reticularis, resulting in excessive
cortisol production (Cushing syndrome).
FINDINGS:
 Hypertension, weight gain, moon facies A, abdominal striae B and truncal obesity,
buffalo hump, skin changes (eg, thinning, striae), osteoporosis, hyperglycemia
(insulin resistance), amenorrhea, and immunosuppression.
DIAGNOSIS:
 Screening tests include:
 ↑ Free cortisol on 24-hr urinalysis,
 ↑ midnight salivary cortisol,
 No suppression with overnight low-dose dexamethasone test.
 Measure serum ACTH.
1) If ↓, suspect adrenal tumor or exogenous glucocorticoids.
2) If ↑, distinguish between Cushing disease and ectopic ACTH secretion
(eg, from small cell lung cancer) with a high-dose dexamethasone
suppression test and CRH stimulation test. Ectopic secretion will not
decrease with dexamethasone because the source is resistant to
negative feedback; ectopic secretion will not increase with CRH
because pituitary ACTH is suppressed.
Adrenal insufficiency:
 Inability of adrenal glands to generate enough glucocorticoids +/- mineralocorticoids
for the body’s needs.
Symptoms
 include weakness, fatigue, orthostatic hypotension, muscle aches, weight loss, GI
disturbances, sugar and/ or salt cravings.
Treatment:
 glucocorticoid/ mineralocorticoid replacement.
Diagnosis:
 involves measurement of serum electrolytes, morning/random serum cortisol and
ACTH (low cortisol, high ACTH in 1° adrenal insufficiency; low cortisol, low ACTH
in 2°/3° adrenal insufficiency due to pituitary/ hypothalamic disease),
 Response to ACTH stimulation test.
 Alternatively, can use metyrapone stimulation test:
 Metyrapone blocks last step of cortisol synthesis (11-deoxycortisol 
cortisol).
 Normal response is ↓ cortisol and compensatory ↑ ACTH and 11-
deoxycortisol.
 In 1° adrenal insufficiency, ACTH is ↑ but 11-deoxycortisol
remains ↓ after test.
 In 2°/3° adrenal insufficiency, both ACTH and 11-deoxycortisol remain ↓
after test.
Primary adrenal insufficiency:

 Deficiency of aldosterone and cortisol production due
to loss of gland function.
 SYMTOMS: Hypotension (hyponatremic volume
contraction), hyperkalemia, metabolic acidosis, skin
and mucosal hyperpigmentation A (due to ↑ MSH, a
byproduct of ACTH production from
proopiomelanocortin [POMC]).
 Acute—sudden onset (eg, due to massive
hemorrhage). May present with shock in acute
adrenal crisis.
 Chronic—aka Addison disease. Due to adrenal atrophy or destruction by disease
(autoimmune destruction most common in the Western world; TB most common in
the developing world).
 Primary Pigments the skin/mucosa.
 Associated with autoimmune polyglandular syndromes.
 UW: The presence of shock in combination with hyponatremia, hyperkalemia, and
hypoglycemia is strongly suggestive of adrenal crisis.
 Waterhouse-Friderichsen syndrome:
 Acute 1° adrenal insufficiency due to adrenal hemorrhage
 Associated with septicemia (usually Neisseria meningitides), DIC, endotoxic
shock.
 UW: Adrenal crisis + fever, vomiting, nuchal rigidity and petechial rash, clinical
signs strongly suggestive of meningococcal meningitis.
Secondary adrenal insufficiency:

 Seen with ↓ pituitary ACTH production.
 No skin/mucosal hyperpigmentation, no hyperkalemia (aldosterone synthesis
preserved due to intact renin-angiotensin-aldosterone axis).
 Secondary Spares the skin/mucosa.
Tertiary adrenal insufficiency:

 Seen in patients with chronic exogenous steroid use, precipitated by abrupt
withdrawal.
 Aldosterone synthesis unaffected.
 Tertiary from Treatment.
Hyperaldosteronism:
 Increased secretion of aldosterone from adrenal gland.
 Clinical features include hypertension, ↓ or normal K+, metabolic alkalosis. No
edema due to aldosterone escape mechanism.
Primary hyperaldosteronism:
 Seen with adrenal adenoma (Conn syndrome) or bilateral adrenal hyperplasia.
 ↑ Aldosterone, ↓ renin.
 UW: Hypokalemic alkalosis  these electrolyte abnormalities can cause
paresthesias and muscle weakness in some patients with primary
hyperaldosteronism.
 UW: Aldosterone escape:
1) The high aldosterone levels lead to increased intravascular volume and
therefore cause increased renal blood flow (with resulting pressure
natriuresis) and augmented release of atrial natriuretic peptide.
This ultimately results in increased sodium excretion by the renal
tubules, which limits net sodium retention and prevents the
development of overt volume overload and significant hypernatremia.
Secondary hyperaldosteronism:
 Seen in patients with renovascular hypertension, juxtaglomerular cell
tumors (renin-producing), and edema (eg, cirrhosis, heart failure, nephrotic
syndrome).
Neuroendocrine tumors:
 Group of neoplasms originating from Kulchitsky and enterochromaffn-like cells.
 Occur in various organs (eg, thyroid: medullary carcinoma; lungs: small cell
carcinoma; pancreas: islet cell tumor; adrenals: pheochromocytoma).
 Cells contain amine precursor uptake decarboxylase (APUD) and secrete different
hormones (eg, 5-HIAA, neuron-specific enolase [NSE], chromogranin A).
Neuroblastoma:
 Most common tumor of the adrenal medulla A in children, usually < 4 years
old.
 Originates from neural crest cells.
 Occurs anywhere along the sympathetic chain.
 Most common presentation is abdominal distension and a firm, irregular mass
that can cross the midline (vs Wilms tumor, which is smooth and unilateral).
 Less likely to develop hypertension than with pheochromocytoma.
 Can also present with opsoclonus-myoclonus syndrome (―dancing eyes-
dancing feet‖).
 ↑ HVA and VMA (catecholamine metabolites) in urine.
 Homer-Wright rosettes B characteristic of neuroblastoma and
medulloblastoma.
 Bombesin and NSE ⊕.
 Associated with overexpression of N-myc oncogene. Classified as an APUD
tumor.
Pheochromocytoma
 ETIOLOGY:
1) Most common tumor of the
adrenal medulla in adults A.
2) Derived from chromaffin cells
(arise from neural crest).
3) May be associated with germline
mutations (eg, NF-1, VHL, RET [MEN 2A,
2B]).
 SYMPTOMS:
1) Most tumors secrete epinephrine, norepinephrine,
and dopamine, which can cause episodic
hypertension.
2) Symptoms occur in “spells‖—relapse and remit.
3) Episodic hyperadrenergic symptoms (5 P’s):
Pressure (↑ BP)
Pain (headache)
Perspiration
Palpitations (tachycardia)
Pallor
 FINDINGS: ↑catecholamines and metanephrines in urine and plasma.
 TREATMENT:
1) Irreversible α-antagonists (eg, phenoxybenzamine) followed by β-
blockers prior to tumor resection.
2) α-blockade must be achieved before giving β-blockers to avoid a
hypertensive crisis.
Hypothyroidism:
Hashimoto thyroiditis:
 Most common cause of hypothyroidism in iodine-
sufficient regions.
 An autoimmune disorder with antithyroid peroxidase
(antimicrosomal) and antithyroglobulin antibodies.
 Associated with ↑ risk of non-Hodgkin lymphoma
(typically of B-cell origin).
 May be hyperthyroid early in course due to thyrotoxicosis
during follicular rupture.
 Histologic findings: Hürthle cells, lymphoid aggregates
with germinal centers A.
 Findings: moderately enlarged, nontender thyroid.
Congenital hypothyroidism (cretinism):

 Causes: maternal hypothyroidism, thyroid agenesis, thyroid dysgenesis (most
common cause in US), iodine deficiency, dyshormonogenetic goiter.
 Findings: Pot-bellied, Pale, Puffy-faced child with Protruding umbilicus, Protuberant
tongue, and Poor brain development: the 6 P’s B C.
Subacute granulomatous thyroiditis (de Quervain):

 Self-limited disease often following a flu-like illness (eg, viral infection).
 May be hyperthyroid early in course, followed by hypothyroidism.
 Histology: granulomatous inflammation  lymphocytic infiltrate with macrophages
and multinucleated giant cells.
 Findings: ↑ ESR, jaw pain, very tender thyroid. (de Quervain is associated with
pain.)
Riedel thyroiditis
 Thyroid replaced by fibrous tissue with inflammatory
infiltrate D.
 Fibrosis may extend to local structures (eg, trachea,
esophagus), mimicking anaplastic carcinoma.
 1⁄3 are hypothyroid.
 Considered a manifestation of IgG4-related systemic
disease (eg, autoimmune pancreatitis, retroperitoneal
fibrosis, and noninfectious aortitis).
 Findings: fixed, hard (rock-like), painless goiter.
 Other causes: Iodine deficiency, goitrogens (eg, amiodarone, lithium), Wolff-

Chaikoff effect (thyroid gland downregulation in response to ↑ iodide).
 UW: Hypothyroid myopathy:
 Myalgia, proximal muscle weakness, and cramping.
 Myoedema (focal mounding of muscle following percussion) is a
characteristic finding that occurs in hypothyroid myopathy secondary to slow
reabsorption of calcium by the sarcoplasmic reticulum.
 Serum CK elevation can precede the development of overt
hypothyroid symptoms by several years. Therefore, hypothyroidism
should be excluded with measurement of TSH levels in all patients
with unexplained CK elevation.
 UW: TSH is the most sensitive marker for diagnosis of hypothyroidism.

 Small changes in thyroid hormone levels lead to marked changes in serum
TSH level.
 In hypothyroidism, the TSH rise occurs well before a low thyroid hormone
level is seen.
Hyperthyroidism
Graves disease:
 Most common cause of hyperthyroidism.
 Thyroid-stimulating immunoglobulin (IgG; type II hypersensitivity) stimulates
TSH receptors on thyroid (hyperthyroidism, diffuse goiter) and dermal fibroblasts
(pretibial myxedema).
 Infiltration of retroorbital space by activated T-cells  ↑ cytokines (eg, TNF-α,
IFN-γ)  ↑ fibroblast secretion of hydrophilic GAGs  ↑ osmotic muscle swelling,
muscle inflammation, and adipocyte count  exophthalmos.
 UW: High-dose glucocorticoids are helpful in decreasing the severity of
inflammation and decreasing extraocular volume.
 Glucocorticoids are also used to prevent worsening of ophthalmopathy
induced by radioactive iodine treatment (particularly common in
smokers).
 Often presents during stress (eg, pregnancy).
 Associated with HLA-DR3 and HLA-B8.
 Tall, crowded follicular epithelial cells; scalloped colloid B.
 UW: Pretibial myxedema and exophthalmos are specific features of

hyperthyroidism due to Graves disease.
 These specific symptoms are not caused by increased thyroid hormone
levels but are instead due to the autoimmune response directed against the
TSH receptor.
 This receptor is widely distributed throughout the body, particularly on
adipocytes and fibroblasts.
 Patients with Graves disease develop lymphocytic infiltration of the orbital
and pretibial connective tissue due to increased TSH receptor expression in
these regions.
 Cytokines released by activated T cells increase fibroblast proliferation and
secretion of glycosaminoglycans, resulting in mucinous edema and tissue
expansion.
Toxic multinodular goiter:

 Focal patches of hyperfunctioning follicular cells distended
with colloid C
 Working independently of TSH (due to TSH receptor
mutations in 60% of cases).
 ↑ Release of T3 and T4.
 Hot nodules are rarely malignant.
Thyroid storm:
 Uncommon but serious complication that occurs when hyperthyroidism is
incompletely treated/ untreated and then significantly worsens in the setting of acute
stress such as infection, trauma, surgery.
 Presents with agitation, delirium, fever, diarrhea, coma, and tachyarrhythmia (cause
of death). May see ↑ LFTs.
 Treat with the 4 P’s: β-blockers (eg, Propranolol), Propylthiouracil, corticosteroids
(eg, Prednisolone), Potassium iodide (Lugol iodine).
Jod-Basedow phenomenon ( iodine-induced hyperthyroidism):

 Hyperthyroidism following administration of iodine or iodide, either as a dietary
supplement or as contrast medium.
 Thyrotoxicosis if a patient with iodine deficiency and partially autonomous thyroid
tissue (eg, autonomous nodule) is made iodine replete. Opposite of Wolff-Chaikoff
effect.
Thyroid neoplasia:
 Usually presents as a distinct, solitary nodule.
 Thyroid nodules are more likely to be benign than malignant.
 Radioactive iodine uptake studies are useful to further characterize nodules.
 Increased uptake ('hot' nodule) is seen in Graves disease or nodular goiter.
 Decreased uptake ('cold' nodule) is seen in adenoma and carcinoma; often
warrants biopsy.
 Biopsy is performed by fine needle aspiration (FNA).
Thyroid adenoma:
 Benign solitary growth of the thyroid.
 Most are nonfunctional (―cold‖), can rarely cause hyperthyroidism via autonomous
thyroid hormone production (―hot‖ or ―toxic‖).
 Most common histology is follicular A;  Surrounded by a fibrous capsule.
 Absence of capsular or vascular invasion (unlike follicular carcinoma).
Thyroid cancer
 Typically diagnosed with fine needle aspiration; treated with thyroidectomy.
 Complications of surgery include:
 Hoarseness (due to recurrent laryngeal nerve damage),
 hypocalcaemia (due to removal of parathyroid glands), and
 Transection of recurrent and superior laryngeal nerves (during ligation of
inferior thyroid artery and superior laryngeal artery, respectively).
Papillary carcinoma:
 Most common, excellent prognosis.
 Exposure to ionizing radiation in childhood is a
major risk factor.
 Pathology:
1) “Orphan Annie‖ eyes empty-appearing
nuclei with central clearing A.
2) PsamMoma bodies.
3) Nuclear grooves (Papi and Moma adopted
Orphan Annie).
 Often spreads to cervical (neck) lymph nodes.
 ↑ Risk with RET and BRAF mutations, childhood irradiation.
Follicular carcinoma:
 Good prognosis.
 Invades thyroid capsule and vasculature (unlike
follicular adenoma).
 FNA only examines cells and not the capsule;
hence, a distinction between follicular adenoma
and follicular carcinoma cannot be made by
FNA.
 Uniform follicles;
 Hematogenous spread is common.
 Associated with RAS mutation.
Medullary carcinoma:
 From parafollicular ―C cells‖; produces calcitonin  May lead to hypocalcemia.
 Calcitonin often deposits within the tumor as amyloid.
 Sheets of cells in an amyloid stroma (stains with Congo red).
 Associated with MEN 2A and 2B (RET mutations).
 UW: The RET proto-oncogene codes for a membrane-bound tyrosine kinase
receptor involved in cell cycle regulation.
 Detection of the RET mutation warrants prophylactic thyroidectomy.
Undifferentiate/ anaplastic carcinoma:

 Older patients; invades local structures (dysphagia or respiratory compromise), very
poor prognosis.
Lymphoma:
 Associated with Hashimoto thyroiditis.
Hypoparathyroidism:
 Due to accidental surgical excision of parathyroid glands, autoimmune destruction,
or DiGeorge syndrome.
 Findings:
 Tetany, hypocalcemia, hyperphosphatemia.
 Chvostek sign—tapping of facial nerve (tap the Cheek)  contraction of
facial muscles.
 Trousseau sign—occlusion of brachial artery with BP cuff (cuff the Triceps)
 carpal spasm.
 UW: These signs of neuromuscular hyperexcitability become clinically
apparent with serum calcium levels <7.0 mg/dL.
Pseudohypoparathyroidism type 1A
(Albright hereditary osteodystrophy):
 Unresponsiveness of kidney to PTH  hypocalcemia despite ↑ PTH levels.
 Characterized by shortened 4th/5th digits, short stature.
 Autosomal dominant.
 Due to defective Gs protein α-subunit causing end-organ resistance to PTH.
 Defect must be inherited from mother due to imprinting.
Pseudopseudohypoparathyroidism:
 Physical exam features of Albright hereditary osteodystrophy but without end-organ
PTH resistance (PTH level normal).
 Occurs when defective Gs protein α-subunit is inherited from father.
Hyperparathyroidism
Primary hyperparathyroidism:
 Usually due to parathyroid adenoma or hyperplasia.
 Hypercalcemia, hypercalciuria (renal stones), polyuria (thrones), hypophosphatemia,
 ↑ PTH, ↑ ALP, ↑ cAMP in urine.
 Most often asymptomatic.
 May present with weakness and
constipation (―groans‖),
abdominal/flank pain (kidney stones, acute pancreatitis), depression (―psychiatric
overtones‖).
 Osteitis fibrosa cystica:
 Cystic bone spaces filled with brown fibrous tissue A
 (―Brown tumor‖ consisting of osteoclasts and deposited hemosiderin from
hemorrhages; causes bone pain).
 Due to ↑ PTH, classically associated with 1° (but also seen with 2°)
hyperparathyroidism.
 UW: subperiosteal erosions in phalanges of the hand, a granular "salt-and-
pepper" skull, and osteolytic cysts in the long bones (osteitis fibrosa cystica).
Secondary hyperparathyroidism:
 2° hyperplasia due to ↓ Ca2+ absorption and/or ↑ PO4-,
 Most often in chronic renal disease (causes hypovitaminosis D and
hyperphosphatemia  ↓ Ca2+).
 Hypocalcemia, hyperphosphatemia in chronic renal failure (vs hypophosphatemia
with most other causes).
 ↑ ALP, ↑ PTH.
 Renal osteodystrophy: renal disease  2° and 3° hyperparathyroidism  bone
lesions.
Tertiary hyperparathyroidism:
 Refractory (autonomous) hyperparathyroidism resulting from chronic renal disease.
 ↑↑ PTH, ↑ Ca2+.
 UW: Clinical picture of hypercalcemia:

 Impaired depolarization of neuromuscular membranes (leading to muscle
weakness, constipation, and mental status changes).
 Impaired concentration of urine in the distal tubule (leading to
polyuria/polydipsia).
 Some patients can also have bone demineralization with associated bone pain.
Familial hypocalciuric hypercalcemia:

 Defective G-coupled Ca2+-sensing (CaSR) receptors in multiple tissues (eg,
parathyroids, kidneys).
 Higher than normal Ca2+ levels required to suppress PTH.
 Excessive renal Ca2+ reuptake  mild hypercalcemia and hypocalciuria with normal to
↑PTH levels.
 Functions of the Calcium-sensing Receptor:
 Parathyroid gland: mediates negative feedback mechanisms relating to PTH
secretion (PTH secretion should decrease if there is a high blood calcium level).
Abnormalities in the CaSR here cause hypercalcemia.
 Kidneys: mediates negative feedback mechanisms relating to calcium
reabsorption from the tubular system (reabsorption should decrease if there is a
high blood calcium level). Abnormalities in the CaSR here cause both
hypercalcemia and hypocalciuria.
Pituitary adenoma:
 Benign tumor, most commonly prolactinoma (arises from
lactotrophs).
 Adenoma A may be functional (hormone producing) or
nonfunctional (silent).
 Nonfunctional tumors present with mass effect (bitemporal
hemianopia, hypopituitarism, and headache).
 Functional tumor presentation is based on the hormone
produced.
 Prolactinoma in women classically presents as galactorrhea, amenorrhea, and ↓ bone
density due to suppression of estrogen.
 Prolactinoma in men classically presents as low libido and infertility.
 Treatment: dopamine agonists (eg, bromocriptine, cabergoline), transsphenoidal
resection.
Nelson syndrome:
 Enlargement of existing ACTH-secreting pituitary adenoma after bilateral
adrenalectomy for refractory Cushing disease (due to removal of cortisol feedback
mechanism).
 Presents with hyperpigmentation, headaches and bitemporal hemianopia.
 Treatment: pituitary irradiation or surgical resection.
Acromegaly:
 Excess GH in adults.
 Typically caused by pituitary adenoma.
 FINDINGS:
 Large tongue with deep furrows, deep voice, large hands and feet, coarsening of
facial features with aging, frontal bossing, diaphoresis (excessive sweating),
impaired glucose tolerance (insulin resistance).
 ↑ Risk of colorectal polyps and cancer.
 ↑ GH in children  gigantism (↑ linear bone growth).
 HF most common cause of death.
 DIAGNOSIS:
 ↑ Serum IGF-1;
 failure to suppress serum GH following oral glucose tolerance test;
 Pituitary mass seen on brain MRI.
 TREATMENT:
 Pituitary adenoma resection.
 If not cured, treat with octreotide (somatostatin analog) or pegvisomant (growth
hormone receptor antagonist), dopamine agonists (eg, cabergoline).
Laron syndrome (dwarfism):

 Defective growth hormone receptors  ↓ linear growth.
 ↑ GH, ↓ IGF-1.
 Clinical features include short height, small head circumference, characteristic facies
with saddle nose and prominent forehead, delayed skeletal maturation, small genitalia.
Diabetes insipidus:
UW: Primary (psychogenic) polydipsia:

 Psychological disorder characterized by increased intake of free water,
leading to hyponatremia and production of a large volume of dilute urine.
 Water restriction will correct the serum sodium levels and lead to a
significant increase in urine osmolality.
Syndrome of inappropriate antidiuretic hormone secretion

(SIADH):
 Characterized by:
1) Excessive free water retention
2) Euvolemic hyponatremia with continued urinary Na+ excretion
3) Urine osmolality > serum osmolality
 Body responds to water retention with ↓ aldosterone and ↑ ANP and BNP  ↑
urinary Na+ secretion  normalization of extracellular fluid volume 
euvolemic hyponatremia.
 Very low serum Na+ levels can lead to cerebral edema (headache, weakness,
altered mental status), seizures. Correct slowly to prevent osmotic
demyelination syndrome (formerly known as central pontine myelinolysis).
 Causes include:
1) Ectopic ADH (eg, small cell lung cancer)
2) CNS disorders/head trauma
3) Pulmonary disease
4) Drugs (eg, cyclophosphamide)
 Treatment: fluid restriction, salt tablets, IV hypertonic saline, diuretics,
conivaptan,
tolvaptan, demeclocycline.
 Increased urine osmolality during water deprivation test indicates psychogenic
polydipsia.
Hypopituitarism:
 Causes:
1) Nonsecreting pituitary adenoma, craniopharyngioma
2) Sheehan syndrome:
a) Ischemic infarct of pituitary following postpartum bleeding.
b) High estrogen levels during pregnancy cause enlargement of the
pituitary gland without a proportional increase in blood supply.
Peripartum hypotension can cause ischemic necrosis of the
pituitary leading to panhypopituitarism.
c) Usually presents with failure to lactate, loss of pubic hair, absent
menstruation, cold intolerance.
3) Empty sella syndrome:
a) Herniation of the arachnoid and CSF into the sella compresses and
destroys the pituitary gland.
b) Pituitary gland is "absent" (empty sella) on imaging.
c) Often idiopathic, common in obese women.
4) Pituitary apoplexy:
a) Sudden hemorrhage of pituitary gland, often in the presence of an
existing
pituitary adenoma.
b) Usually presents with sudden onset severe headache, visual
impairment (eg,
bitemporal hemianopia, diplopia due to CN III palsy), and features
of hypopituitarism.
c) Treatment: Glucocorticoid replacement (critical to prevent life-
threatening hypotension) • Surgical decompression for persistent
visual symptoms.
5) UW: Lymphocytic hypophysitis:
a) The most common inflammatory condition of the pituitary.
b) Typically occurs during late pregnancy or the early postpartum
period.
c) In contrast to Sheehan syndrome, the presentation is acute with
severe
headaches and visual field defects.
6) Brain injury.
7) Radiation.
 Treatment: hormone replacement therapy (corticosteroids, thyroxine, sex
steroids, human growth hormone).
Diabetes mellitus:
ACUTE MANIFESTATIONS:
 Polydipsia, polyuria, polyphagia, weight loss, DKA (type 1), hyperosmolar coma
(type 2).
 Rarely, can be caused by unopposed secretion of GH and epinephrine. Also seen
in patients on glucocorticoid therapy (steroid diabetes).
CHRONIC COMPLICATIONS:
 Nonenzymatic glycation:
1) Small vessel disease (diffuse thickening of basement membrane) 
a) Retinopathy (hemorrhage, exudates, microaneurysms, vessel
proliferation),
b) glaucoma,
c) neuropathy,
d) Nephropathy (nodular glomerulosclerosis, aka Kimmelstiel-
Wilson nodules  progressive proteinuria [initially
microalbuminuria; ACE inhibitors are renoprotective] and
arteriolosclerosis  hypertension; both lead to chronic renal
failure).
2) Large vessel atherosclerosis:
a) CAD, peripheral vascular occlusive disease, gangrene  limb loss,
cerebrovascular disease.
b) MI most common cause of death.
 Osmotic damage (sorbitol accumulation in organs with aldose reductase and ↓ or
absent sorbitol dehydrogenase):
1) Neuropathy (motor, sensory [glove and stocking distribution], and
autonomic degeneration)
2) Cataracts.
 UW: Pathogenesis of DM complications:
1) Advanced glycosylation end products:
a) Glycosylation refers to the attachment of glucose to amino acid
residues in various proteins forming reversible glycosylation
products that slowly stabilize to irreversible products.
b) Glycosylation products accumulate and cross-links with collagen
in blood vessel walls and interstitial tissues contributing to
microangiopathy and nephropathy.
c) Cross-linking of proteins by glycosylation products also facilitates
inflammatory cell invasion and deposition of LDL in the vascular
walls leading to atherosclerosis.
2) Polyol pathway impairment:
a) Occurs in tissues that do not depend on insulin for glucose
transport (lens, peripheral nerves, blood vessels and kidneys).
b) Hyperglycemia results in increased intracellular glucose

concentrations in these tissues.
c) Glucose undergoes conversion into sorbitol by aldose reductase,
and sorbitol, in turn, is converted into fructose.
d) Sorbitol and fructose increase the osmotic pressure in tissues and
stimulate the influx of water leading to osmotic cellular injury.
e) Increased water in lens fiber cells leads to rupture of these cells
with resultant opacification of the lens and cataract formation.
f) Osmotic injury of Schwann cells contributes to peripheral
neuropathy in diabetes.
 DIAGNOSIS
 UW: Pathogenesis of type 1 DM:

 Occurs in genetically susceptible individuals who are exposed to triggering
environmental factors (eg, viral infections, environmental toxins, dietary
components).
 This results in an autoimmune response against pancreatic beta cells that leads to
progressive loss of beta cell mass.
 Overt manifestations of diabetes mellitus tend to develop once >90% of beta
cells are destroyed.
 Although antibodies against islet antigens are detected in a large number of
patients, they are thought to play a permissive role in disease pathogenesis; the
destruction of beta cells occurs primarily through cell-mediated immunity.
 Infiltration of islets by inflammatory cells is called insulitis and is more
prominent during the early stages of disease.
 UW: Pancreatic islet amyloid deposition is characteristic of type 2 diabetes mellitus.

 Amylin is stored in insulin secretory granules and is co-secreted with insulin
from pancreatic beta cells.
 The two cardinal defects involved in the pathophysiology of type 2 diabetes
mellitus are increased insulin resistance and defective insulin secretion.
 Amylin may play a causative role in beta cell apoptosis and defective insulin
secretion.
Diabetic ketoacidosis (DKA):

 One of the most feared complications of diabetes.
 Usually due to insulin noncompliance or ↑ insulin requirements from ↑ stress (eg,
infection).
 Excess fat breakdown and ↑ ketogenesis from ↑ free fatty acids, which are then
made into ketone bodies (β-hydroxybutyrate > acetoacetate).
 Usually occurs in type 1 diabetes, as endogenous insulin in type 2 diabetes
usually prevents lipolysis.
 SIGNS/SYMPTOMS DKA is Deadly:
1) Delirium/psychosis,
2) Kussmaul respirations (rapid/deep breathing),
3) Abdominal pain/nausea/vomiting, Dehydration.
4) Fruity breath odor (due to exhaled acetone).
 LABS:
1) Hyperglycemia, ↑ H+, ↓ HCO3– (↑ anion gap metabolic acidosis),
2) ↑ Blood ketone levels, leukocytosis.
3) Hyperkalemia, but depleted intracellular K+ due to transcellular shift
from ↓ insulin and acidosis (therefore total body K+ is depleted).
 COMPLICATIONS:
1) Life-threatening mucormycosis (usually caused by Rhizopus infection),
2) cerebral edema,
3) Cardiac arrhythmias, heart failure.
 TREATMENT: IV fluids, IV insulin, and K+ (to replete intracellular stores);
glucose if necessary to prevent hypoglycemia.
 UW: the body perceives DKA as hypoglycemia despite high level of glucose?!!
Due to no insulin to transport glucose inside the cell  ↑glucagon  ↑ketone
bodies.
Hyperosmolar hyperglycemic state:

 State of profound hyperglycemia-induced dehydration and ↑ serum osmolality.
 Classically seen in elderly type 2 diabetics with limited ability to drink.
 Hyperglycemia  excessive osmotic diuresis  dehydration  eventual onset of
HHNS.
 Symptoms: thirst, polyuria, lethargy, focal neurological deficits (eg, seizures),
can progress to coma and death if left untreated.
 Labs:
1) Hyperglycemia (often > 600 mg/dL),
2) ↑ serum osmolality (> 320 mOsm/kg),
3) No acidosis (pH > 7.3, ketone production inhibited by presence of insulin).
 Treatment: aggressive IV fluids, insulin therapy.
UW: The 3 most important predisposing factors for hypoglycemia in patients with type 1
diabetes are:
1. Excessive insulin dose,
2. inadequate food intake, and
3. Physical activity/exercise.
UW: Symptoms of hypoglycemia:

1. Neurogenic symptoms: are caused by sympathoadrenal activation and are
mediated via norepinephrine/epinephrine and acetylcholine released by
sympathetic postganglionic nerve fibers:
 Symptoms of norepinephrine/epinephrine release include
tremulousness, palpitations, and anxiety/arousal,
 Whereas cholinergic symptoms include sweating, hunger, and
paresthesias.
2. Neuroglycopenic symptoms include behavioral changes, confusion, visual
disturbances, stupor, and seizures.
UW: Beta Blockers and diabetes:

1. Non-selective β-blockers (eg. propranolol, timolol, nadolol) inhibit
norepinephrine/epinephrine-mediated compensatory reactions to hypoglycemia
(cholinergic symptoms are unaffected).
2. In addition, blockade of β2-adrenergic receptors inhibits hepatic gluconeogenesis
and peripheral glycogenolysis and lipolysis  increase the risk of hypoglycemia.
3. Selective β1-blockers and β-blockers with intrinsic sympathomimetic activity (eg,
carvedilol) are preferred for diabetics as these have minimal effect on glucose
metabolism and adrenergic symptoms.
UW: Severe hypoglycemia with loss of consciousness is typically treated with

intramuscular glucagon in the nonmedical setting and with intravenous dextrose in the
medical setting.
UW: Fetal effects of gestational diabetes mellitus :

1. Poor maternal glucose control leads to excessive transplacental glucose transfer
to the fetus, which stimulates fetal insulin production.
2. Chronic stimulation of the fetal beta cells leads to beta cell hyperplasia and
hyperinsulinism.
3. Elevated insulin levels contribute to increased fat deposition and enhanced fetal
growth, resulting in macrosomia.
4. After delivery, the infant experiences a sudden interruption in transplacental
glucose transfer, but the hyperinsulinism remains due to the beta cell hyperplasia.
This can result in rapid development of profound hypoglycemia.
Glucagonoma:
 Tumor of pancreatic α cells  overproduction of glucagon.
 Presents with dermatitis (necrolytic migratory erythema), diabetes (hyperglycemia),
DVT, declining weight, depression.
 UW: necrolytic migratory erythema:
 An elevated painful and pruritic rash.
 Typically affecting the face, groin, and extremities.
 Overtime, small erythematous papules/plaques coalesce to form large lesions with
central clearing of bronze-colored induration.
 The rash also commonly affects the mucus membranes, leading to glossitis,
cheilitis, and blepharitis.
 Treatment: octreotide, surgery.
Insulinoma
 Tumor of pancreatic β cells  overproduction of insulin  hypoglycemia.
 May see Whipple triad:
 Low blood glucose,
 symptoms of hypoglycemia (eg, lethargy, syncope, diplopia), and
 Resolution of symptoms after normalization of glucose levels.
 Symptomatic patients have ↓ blood glucose and ↑ C-peptide levels (vs exogenous insulin
use).
 ∼ 10% of cases associated with MEN 1 syndrome. Treatment: surgical resection.
Somatostatinoma:
 Tumor of pancreatic δ cells  overproduction of somatostatin  ↓ secretion of secretin,
cholecystokinin, glucagon, insulin, gastrin, gastric inhibitory peptide (GIP).
 May present with:
 ↓Pancreatic enzymes/hormones: diabetes/glucose intolerance, steatorrhea,
 ↓CCK  gallstones, and
 ↓Gastrin  achlorhydria.
 Treatment: surgical resection; somatostatin analogs (eg, octreotide) for symptom
control.
Carcinoid syndrome:
 Rare syndrome caused by carcinoid tumors (neuroendocrine
cells).
 Malignant transformations of neuroendocrine cells, most
commonly located in the gastrointestinal tract (eg, small
intestine, rectum, appendix), followed by the
bronchopulmonary system.
 Most common malignancy in the small intestine.
 Histology:
 Prominent rosettes [arrow]. Composed of
islands or sheets of uniform cells with
eosinophilic cytoplasm and oval-to-round
stippled nuclei.
 Cells: Fried egg like appearance
 Prominent in metastatic small bowel tumors, which
secrete high levels of serotonin (5-HT). Not seen if
tumor is limited to GI tract (5-HT undergoes first-pass metabolism in liver).
 Appendiceal carcinoids typically have a benign course but may cause appendicitis or,
rarely, carcinoid syndrome (eg, with liver metastasis).
 C/P:
 Skin: flushing, telangectasias, cyanosis
 GIT: watery diarrhea, cramping
 Pulmonary: bronchospasm, dyspnea, wheezing
 Cardiac: valvular fibrous plaques (right > left)
 Dx: ↑5-hydroxyindoleacetic acid (5-HIAA) in urine, niacin deficiency (pellagra).
 Treatment: surgical resection, somatostatin analog (eg, octreotide).
 Rule of 1/3s: 1/3 metastasize & 1/3 present with 2nd malignancy & 1/3 are multiple.
Zollinger-Ellison syndrome:
 Gastrin-secreting tumor (gastrinoma) of pancreas or duodenum.
 Acid hypersecretion causes recurrent ulcers (beyond the duodenal pulp or
resistant to treatment).
 Presents with abdominal pain (peptic ulcer disease), diarrhea (malabsorption)
because pancreatic/intestinal enzymes are inactivated by gastric acid and cannot
digest nutrients properly.
 Positive secretin stimulation test: gastrin levels remain elevated after administration
of secretin, which normally inhibits gastrin release.
 Administration of exogenous secretin stimulates gastrin release from
gastrinomas and can be used to differentiate ZES from other causes of
hypergastrinemia (eg, atrophic gastritis).
 In contrast, secretin inhibits release of gastrin from normal gastric G cells.
 May be associated with MEN 1.
ENDOCRINE PHARMACOLOGY:
 Diabetes mellitus management: Treatment strategies:
 Type 1 DM—dietary modifications, insulin replacement.
 Type 2 DM—dietary modifications and exercise for weight loss; oral agents,
non-insulin injectables, insulin replacement
 Gestational DM (GDM)—dietary modifications, exercise, insulin
replacement if lifestyle modification fails.
 Short-acting regular human insulin:

 Starts working 30 minutes after subcutaneous injection.
 Peak effects occurring between 2-4 hours.
 Unfortunately, the peak effect of regular insulin occurs after the postprandial
peak in blood glucose concentration.
 This mismatch between the insulin and glucose peaks generally leads to
inadequate control of glucose following meals.
 Rapid-acting insulins were produced to overcome this problem.
 Their onset of action is under 15 minutes and peaks between 45-75 minutes, a
pattern that closely mimics the endogenous postprandial insulin response of
normal individuals.
Oral hypoglycemic drugs:

Biguanides (Metformin):
 Clinical use:
 Oral. First-line therapy in type 2 DM.
 Causes modest weight loss.
 Can be used in patients without islet function.
 Mechanism of action:
 Inhibit hepatic gluconeogenesis and the action of glucagon.
 ↓ Gluconeogenesis.
 ↑ Glycolysis, ↑ peripheral glucose uptake (↑ insulin sensitivity).
 Side effects:
 GI upset.
 Most serious adverse effect is lactic acidosis (thus contraindicated in
renal insufficiency).
 UW: Metformin:
 Inhibits mitochondrial glycerophosphate dehydrogenase and complex I
(first electron transport chain enzyme).
 The resulting decrease in cellular energy stores causes AMPK (adenosine
monophosphate-activated protein kinase) activation, leading to decreased
hepatic gluconeogenesis.
 Metformin also increases peripheral glucose utilization.
 It does not increase endogenous insulin secretion and does not cause
hypoglycemia when used as monotherapy.
 In normal individuals, lactate produced in the intestine is converted to glucose
via gluconeogenesis in the liver.
 Inhibition of mitochondrial enzymes by metformin increases intestinal
production of lactate (due to increased anaerobic glycolysis) and reduces
hepatic metabolism of lactic acid (due to decreased gluconeogenesis).
 This increases the risk of lactic acidosis, particularly in older patients and
those with significant hepatic or renal dysfunction.
 Renal function should be assessed by serum creatinine measurement prior
to initiation of metformin therapy.
 Metformin should also be avoided in patients with congestive heart failure or
alcoholism due to the increased risk of lactic acidosis in these populations.
Sulfonylureas & Glitazones
 UW: Glyburide and glimepiride are long-acting and have a higher incidence of
hypoglycemia, especially in the elderly. In contrast, glipizide is short-acting and has
a significantly lower incidence of hypoglycemia.
 K: Glipizide  ↓dose in hepatic failure.
Glyburide  ↓ dose in renal failure.
 K: Repaglinide has an action similar to sulfonylurea closing K channels.
 K: What thing u should do before starting oral hypoglycemic?  LFTs.
 UW: Important genes that are upregulated by TZDs include:

 Glucose transporter-4 (GLUT4).
 Adiponectin: a cytokine secreted by fat tissue that increases the number of
insulin-responsive adipocytes and regulates fatty acid oxidation.
 UW: it takes several days to a few weeks after commencing TZD therapy to observe
a significant reduction in glucose levels because the glucose-lowering effect of TZDs
requires alterations in gene transcription and protein synthesis.
 UW: The main side effect of TZDs is fluid retention due to increased sodium
reabsorption in the renal collecting tubules. This can lead to water weight gain,
peripheral edema, and decompensation of underlying congestive heart
failure. Fluid retention is often worse when TZDs are given in combination with
insulin. TZDs also cause adipose weight gain, likely due to a combination of
increased fat storage in adipocytes and an increased number of adipocytes in
subcutaneous tissue.
UW: It is recommended to monitor serum creatinine before and after initiating therapy with
SGLT2 inhibitors.
UW: Glucagon-like polypeptide-1 (GLP-1):
 Is secreted by intestinal L cells in
response to food intake.
 Regulates glucose by decreasing gastric emptying and increasing insulin
release.
Anti-Thyroid drugs:
 Thioamides: Propylthiouracil, methimazole.

 MECHANISM:
1) Block thyroid peroxidase, inhibiting the oxidation of iodide and the
organifcation and coupling of iodine  inhibition of thyroid hormone
synthesis.
2) Propylthiouracil also blocks 5′-deiodinase  ↓ peripheral conversion
of T4 to T3.
 CLINICAL USE:
1) Hyperthyroidism.
2) PTU used in first trimester of pregnancy (due to methimazole
teratogenicity);
3) Methimazole used in second and third trimesters of pregnancy (due
to risk of PTU-induced hepatotoxicity).
 ADVERSE EFFECTS: Skin rash, agranulocytosis (rare), aplastic anemia,
and hepatotoxicity. Methimazole is a possible teratogen (can cause aplasia
cutis).
 UW: If agranulocytosis is suspected, the eliciting drug should be
discontinued immediately and a white blood cell count with differential
obtained to confirm the diagnosis.
UW: Potassium iodide:

 Competitively inhibits thyroid uptake of radioactive iodine isotopes and is
often administered following nuclear accidents to protect the thyroid and
prevent development of radiation-induced thyroid carcinoma.
 High serum levels of nonradioactive iodide can competitively inhibit
radioactive Iodine from entering thyroid follicular cells.
 Large increases in serum iodide levels also inhibit iodine organifcation
(Wolff-Chaikoff effect) and reduce thyroid hormone release.
 Radioactive iodine results in radiation-induced hypothyroidism and thyroid
carcinoma (particularly in younger patients).
Levothyroxine, triiodothyronine:
 MECHANISM: Thyroid hormone replacement.
 CLINICAL USE: Hypothyroidism, myxedema. Used off-label as weight loss
supplements.
 ADVERSE EFFECTS: Tachycardia, heat intolerance, tremors, arrhythmias.
Hypothalamic/pituitary drugs:
 ADH antagonists (conivaptan, tolvaptan)  SIADH, block action of ADH at V2-
receptor.
 Desmopressin acetate  Central (not nephrogenic) DI, von Willebrand disease,
sleep enuresis.
 UW: Von Willibrand's disease:
1) Tooth extraction crazy bleeding
2) Lots of bruises
3) Rx = Desmopressin acetate - releases vWF and VIII:c from endothelial
cells.
4) Only mild forms of disease respond to desmopressin acetate
 GH  GH deficiency, Turner syndrome.
 Oxytocin  Stimulates labor, uterine contractions, milk let-down; controls uterine
hemorrhage.
 Somatostatin (octreotide)  Acromegaly, carcinoid syndrome, gastrinoma,
glucagonoma, esophageal varices.
Demeclocycline:
 MECHANISM: ADH antagonist (member of tetracycline family).
 CLINICAL USE SIADH.
 ADVERSE EFFECTS Nephrogenic DI, photosensitivity, abnormalities of
bone and teeth.
Fludrocortisone:
 MECHANISM: Synthetic analog of aldosterone with little glucocorticoid effects.
 CLINICAL USE: Mineralocorticoid replacement in 1° adrenal insufficiency.
 ADVERSE EFFECTS: Similar to glucocorticoids; also edema, exacerbation of heart
failure, hyperpigmentation.
Cinacalcet:
 MECHANISM: Sensitizes Ca2+-sensing receptor (CaSR) in parathyroid gland to
circulating Ca2+  ↓ PTH.
 CLINICAL USE: 1° or 2° hyperparathyroidism.
 ADVERSE EFFECTS: Hypocalcemia.
Bisphosphonates:
 (Alendronate, ibandronate, risedronate, zoledronate)
 Inhibit mature osteoclast-mediated bone resorption.
 Have a chemical structure similar to pyrophosphate and attach to hydroxyapatite
binding sites on bony surfaces.
 Osteoclasts that resorb the bone take up the bisphosphonate and are unable to adhere
to more bony surfaces to continue resorption.
 Bisphosphonates decrease osteoclast activity, induce osteoclast apoptosis, and
decrease development/recruitment of osteoclast precursor cells.
 The net result of inhibiting bone resorption and increasing osteoclast apoptosis is to
slow the rate of bone loss, and some patients may experience a small increase in
bone mineral density.
 CLINICAL USE:
 Osteoporosis, hypercalcemia, Paget disease of bone, metastatic bone disease,
osteogenesis imperfecta.
 ADVERSE EFFECTS:
 Esophagitis (if taken orally, patients are advised to take with water and
remain upright for 30 minutes), osteonecrosis of jaw, atypical stress fractures.
 Endocrine pancreas cell types P4 “add 2 cells ”:
ε =Epsilon cells produce the hormone ghrelin .
PP = gamma cells or F cells producing pancreatic polypeptide.
 Signaling pathways of endocrine hormones P.28

1. Serine/threonine
2. kinase receptor
3. TGF-β
 Primary polydipsia and diabetes insipidus P. 50
- Characterized by the production of large amounts of dilute urine +/– thirst. Urine specific gravity <1.006. Urine
osmolality usually <300 mOsm /kg. Diabetes insipidus (DI) is classified as central or nephrogenic depending on
etiology.
 Cation exchange resin
 Hyperglycemic emergencies P.58

- Usually occurs in patients treated with insulin or insulin secretagogues .
(eg. sulfonylureas, meglitinides) in the setting of high-dose treatment, inadequate food intake, and/or exercise.
- Neurogenic/autonomic symptoms: diaphoresis, tachycardia, tremor, anxiety, hunger. May allowperception of
glucose (hypoglycemia awareness) .
Neuroglycopenic symptoms: altered mental status, seizures, death due to insufficient glucose in
CNS .
- Treatment: simple carbohydrates (eg , glucose tablets, fruit juice), IM glucagon, IV dextrose.
 Acute adrenal insufficiency p.33

Also called adrenal (addisonian crisis) often precipitated by acute stressors that increase requirements (eg, infection)
in patients with pre-existing adrenal insufficiency or on steroid therapy. May present with acute abdomen, nausea,
vomiting, altered mental status, shock.
Waterhouse-Friderichsen syndrome—bilateral adrenal hemorrhage often due to
meningococcemia. May present with acute adrenal insufficiency, fever, petechiae, sepsis.
 GLUT-4 transporter transfer occur via facilitated diffusion, it is stereo-selective,
more catalyze the entrance of D-glucose rather than L-glucose into the cells.
 The effect of leptin ↓↓ production of neuropeptide Y which is a potent appetite

stimulant (in the arcuate nucleus) and↑ production of POMC in the arcuate
nucleus → ↑↑ α-MSH and inhibit food intake.
 The role of ACTH in cortisol synthesis is ↑↑ transfer of cholesterol to inner

mitochondrial membrane by steroidogenic acute regulatory protein.
And Conversion of cholesterol to pregnenolone by side chain cleavage enzyme.
‫ـــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
‫ــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــــ‬
 Signaling of CaSRis a G-protein bound receptors in many tissue including the
parathyroid, then bind of Ca → inhibition of the production of PTH.
 Difference in role of PTH, Vitamin D3 in calcium/ phosphate homeostasis is

1. PTH: responsible for min. to min. Concentration
2. Vitamin D3: responsible for long term homeostasis.
 Thyroid hormones 70% bound to TBG in the blood.
 Transtherytin → estrogen ↑ ↑ TGB, but the patient remain euthyroid with TSH level
return to normal range.
 Difference between receptor tyrosine kinase and non receptor (cytoplasmic) tyrosine
kinase:
 Mechanism of tanning in ACTH excess:

1. Co-secretion of α- MSH (same origin POMC)
2. Direct stimulation of MC2R receptor on melanocyte by ACTH
 Specific characters of paraneoplastic Cushing syndrome & causes:

1. Due to ↑↑ ACTH → skin tanning as in Addison’s disease
2. Unlike cushing syndrome , Weight loss is more common than central obesity
3. Associated with SCLC, pancreatic & bronchial carcinoid
 Treatment of Grave’s ophthalmopathy, mechanism of action:

 Treated by glucocorticoids by →
- ↓↓ peripheral conversion of T4 → T3.
- Anti-inflammatory effect → ↓↓ extra-ocular volume.
- Prevent worsening of the ophthalmopathy induced by radio-active iodine.
 What are the Hurthle cells in Hashimoto thyroiditis: large oxyphilic cells filled with
granular cytoplasm that represent follicular epithelial cells that undergone
metaplastic changes due to inflammation.
 Pre-operative assessment of patient with Medullary Tyroid Carcinoma (MTC):

1. You should assess the presence of undiagnosed pheochromatocytoma, as anesthetics
can induce ↑↑ catecholamines → hypertensive crisis, AF, flash PE.
 Diagnosis and metastases of Neuroblastoma :
1. ↑↑↑ catecholamines (VMA/ HVA) (due to neural crest origin).

2. NSE, chromogranin, syaptophysin, S-100 positive.
3. biopsy show : (neuritic process (neuropil, pathognnomonic), small round blue
cells & Homer wright rosettes (also in medulloblastoma, commonest malignant
brain tumor in children) → test for N-myc on chromosome 2(poor prognosis).
 DeQuirivan thyroiditis:
- Histopatholgy of -- : note the multi nucleated giat cells
- Pathogenesis of – cross reacting immune response againse viral protein released
during cellular injury → destruction of the thyroid follicles.
 The histological appearance of anaplastic thyroid carcinoma :

1. markedly pleomorphic cells, irregular giant cells and biphasic spindle cells.
 Diseases that associated with ↑↑ vitamin D :

1. Sarcoidosis (granulomatous diseases)
2. Hodgkin & non Hodgkin lymphoma
 What is the inheritance pattern of CAH ?

1. All are AR disorders, 90% are due to 21α.
 The clinical picture of Sheehan syndrome

1. The first manifestation is failure to lactate after delivery
2. Signs of adreno-cortical deficiency occur rapidly with nausea & vomiting
 Signs of hypothyroidism occur delayed onset, due to ↑↑ t½ of thyroid hormone

(1 week), peripheral conversion of the T4 → T3
 The glitazones have delayed onset of activity may reach to few weeks after
initiation as it affect the transcription factors.
 Dyslipidemia associated with insulin resistance, ↑↑ TGs, low HDL and no change in
LDL .
 Mechanism of ↑↑ K level in case of DKA is (+) due to diuresis → ↓↓ intracellular water

content → ↑↑ ECF osmolarity → pull the K out of the cells.
 What is the inheritance pattern ?

1. All are AR disorders, 90% are due to 21α.
 Describe the use of GnRH in infertility:

Infertility due to hypogonadism is common, treated by pulsatile administration of GnRH
by rogrammed pump to deliver physiological dose every 90 min. → ovulation usually
occur in 10 – 20 days in most women.
 Treatment of Grave’s ophthalmopathy, mechanism of action:

 Treated by glucocorticoids by →
- ↓↓ peripheral conversion of T4 → T3.
- Anti-inflammatory effect → ↓↓ extra-ocular volume.
- Prevent worsening of the ophthalmopathy induced by radio-active iodine.

11 - Endocrine - 2021 Edition Endpoints

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USMLE ENDPOINT ENDOCRINE

1 Page Dr Ahmed Shebl

Adrenal cortex and medulla:

2 Page Dr Ahmed Shebl

3 Page Dr Ahmed Shebl

5) UW: Neurophysins are carrier proteins for oxytocin and vasopressin

Thyroid gland anatomy:

4 Page Dr Ahmed Shebl

UW: Nerve supply of the larynx:

5 Page Dr Ahmed Shebl

6 Page Dr Ahmed Shebl

7 Page Dr Ahmed Shebl

8 Page Dr Ahmed Shebl

9 Page Dr Ahmed Shebl

11 Page Dr Ahmed Shebl

 UW: Mutations in Pancreatic ATP sensitive potassium channel:

11 Page Dr Ahmed Shebl

 UW: Causes of insulin resistance:

 UW: Acanthosis nigricans is one of the signs of insulin resistance.

12 Page Dr Ahmed Shebl

13 Page Dr Ahmed Shebl

UW: ↑Prolactin  ↑risk of bone fracture. AS ↑prolactin  ↓GnRH  ↓estrogen 

14 Page Dr Ahmed Shebl

Growth hormone (somatotropin):

15 Page Dr Ahmed Shebl

Leptin decreases food intake in the following important ways:

16 Page Dr Ahmed Shebl

17 Page Dr Ahmed Shebl

Adrenal steroids and congenital adrenal hyperplasia:

18 Page Dr Ahmed Shebl

UW: Treatment of congenital adrenal hyperplasia involves low doses of exogenous

UW: 5-α reductase deficiency:

 There are 2 types of 5a-reductase:

19 Page Dr Ahmed Shebl

 UW: High doses of corticosteroid therapy can sometimes cause corticosteroid-induced

21 Page Dr Ahmed Shebl

21 Page Dr Ahmed Shebl

 24, 25-(OH)2 D3 is an inactive form of vitamin D.

22 Page Dr Ahmed Shebl

 UW: Osteoprotegerin (OPG) is a physiologic decoy receptor that decreases

23 Page Dr Ahmed Shebl

 UW: In chronic kidney disease, conversion of 25-hydroxyvitamin D to 1,25-

24 Page Dr Ahmed Shebl

Thyroid hormones (T3/T4)

25 Page Dr Ahmed Shebl

 Thyroxine-binding globulin (TBG) binds most T3/T4 in blood; only free

26 Page Dr Ahmed Shebl

 UW: Thyroid hormone exists in 3 forms:

27 Page Dr Ahmed Shebl

Signaling pathways of endocrine hormones:

28 Page Dr Ahmed Shebl

Signaling pathway of steroid hormones:

 UW: Calcium-sensing receptors (CaSR) are transmembrane G-protein-coupled

29 Page Dr Ahmed Shebl

31 Page Dr Ahmed Shebl

31 Page Dr Ahmed Shebl

32 Page Dr Ahmed Shebl

Primary adrenal insufficiency:

Secondary adrenal insufficiency:

Tertiary adrenal insufficiency:

33 Page Dr Ahmed Shebl

34 Page Dr Ahmed Shebl

35 Page Dr Ahmed Shebl