UB Endocrinology

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Normal blood glucose: 90-180 mg/dl
Normal plasma Ca2+: 9-11 mg/dl
Na+/K+ homeostasis: Aldosterone
RAAS
ANP
Calcium homeostasis: PTH
Calcitonin
Calcitriol
Water homeostasis: ADH
Thirst
Blood glucose control: Insulin
Glucagon
GH
Epinephrine
Cortisol
Thyroxine
Basal metabolic rate: Thyroxine
Growth control: GH
IGF
Thyroid hormones
Gonadal function: LH
FSH
Estrogens
Androgens
Progesterone
Lactation: Prolactin
Oxytocin
Pregnancy: LH
FSH
hCG
Progesterone
Estrogen
GI function control: Pepsin and acid
Gastrin
Bicarbonate
Secretin
Bile and pancreatic enzymes
CCK
Somatostatin
Peptide hormones: TRH
GnRH
GH
FSH
LH
TSH
ACTH
Insulin
Glucagon
PTH
Prolactin
CAL
Amino acid derivative hormones: Without iodine - DA, NE, E
With iodine - T4, T3
Steroid hormones: Estradiol
Testosterone
Progesterone
Cortisol
Aldosterone
1,25-DHCC
Thyroid hormone biosynthesis: Iodide (TPO) --> iodine (TPO) --> iodination of tyrosine residues of thyroglobulin (TPO) --> coupling of MIT and DIT

Occurs at the apical membrane of the cell

Iodine salvage -> thyroidal dehalogenase
Epinephrine synthesis: Occurs due to the presence of PNMT in the adrenal medulla

PNMT induced by high concentrations of glucocorticoids

Stored complexed to ATP in chromaffin cells
Steroid hormone sythesis: C27 -> C21 -> C19 -> C18

Pregnenolone (C21) precursor of all the steroid hormones

C21 - progesterone, corticosteroids
C19 - androgens
C18 - estrogens

Added oxygen from CYP450s
Permissive interaction: Hormone A has a robust action, whereas hormone B has little or no action, but w/o hormone B, hormone A has only weak action

Ex: Thyroid hormone and IGF-1 on bone growth
Synergistic interaction: Effect of hormone A and B together is greater than the additive effect of either alone
Inhibitory interaction: Hormone B opposes the action of hormone A

Action is at physiologic receptor B

Ex: insulin and glucagon or GHRH and somatostatin
Diabetes insipidus: Neurogenic (hypothalamic)
Nephrogenic (normal or high ADH)
Psychogenic
Panhypopituitarism: Low TSH
Low ACTH
Low gonadotropins
Low GH
Cushing's disease: Excess ACTH
Gigantism: Increased GH in childhood
Acromegaly: GH excess in adults
Insidious onset
Pulsatile nature of GH secretion complicates Dx
Slow proliferation of soft tissue and cartilage
Bone growth of hands, feet, skull
Visceral and cutaneous growth
HTN, insulin resistance
HA
Dx - increased basal fasting GH, failure of GH to suppress to <2 following 100 g glucose, elevated IGF-1
In acromegaly - L-dopa suppresses GH (normally increases)
Tx - surgery, radiation, octreotide, DA agonists
Primary hyperaldosteronism: Increased aldosterone secretion by ZG
Adenoma > idiopathic > micronodular hyperplasia
volume expansion, HTN, low PRA
Hyperparathyroidism: Tumor or hyperplasia
Rickets and osteomalacia: Kidneys
25-hydroxycholecalciferol-1alpha-hydroxylase deficiency
Nephrogenic diabetes insipidus: Defective ADH receptor system
G alpha s: Stimulatory to adenylate cyclase to synthesize cAMP which stimulates PKA

Ex: beta receptors, calcitonin, PTH, ADH, ACTH, FSH, LH, TSH, glucagon
G alpha i: Inhibitory to adenylate cyclase which inhibits PKA

Ex: alpha 2 receptors
G alpha q: Stimulates activity of phospholipase C which leads to DAG and IP3 production

Ex: alpha 1 receptors, oxytocin, hypothalamic hormones, several eicosanoids
GEF vs. GAP vs. GDI: GEF - guanine nucleotide exchange factor

GAP - GTPase accelerating protein

GDI - guanine nucleotide dissociation inhibitor
Signal termination: Degradation of messenger - PDE
Receptor inactivation
Sequestration
Degradation/downregulation
G protein diseases: Highly specific (mutation) to widespread effects (subunits)
Hereditary defects
Acquired diseases (cholera, whooping cough)
Tumor formation
Receptor tyrosine kinases: EGF receptors, PDGF receptors, insulin receptors
Phosphorylation of MAPK and of transcription factors

Grb2 -> Ras-GEF -> RAS -> MAPKKK -> MAPKK -> MAPK
Tyrosine kinase associated receptors: Do not possess intrinsic enzymatic activity but are associated with intracellular proteins that have tyrosine kinase activity

JAK-STAT pathway
JAK - Janus kinases
STAT - signal transducers and activators of transcription

Also activate RAS pathway

Ex: cytokine receptors, GH, prolactin
Nuclear hormone receptors: Steroids
Thyroid hormone
Retinoids
FA derived (linolenic, AA)

Regulate rate of transcription
Function as hormone regulating trans-acting TFs
Interaction sites called HREs
Nucleosome rearrangement is catalyzed by acetylation of histones by the coactivator proteins
Corepressor proteins deacetylate histones thereby compacting nucleosomes and making the TATA box inaccessible

Type 1 - requires ligand binding for DNA binding
Type 2 - requires ligand binding for activation
Domains of nuclear hormone receptors: HIGHLY CONSERVED
LBD - hormone specific binding domain (C terminal)
-TAF2 - activation function domain - hormone dependent
DBD - DNA binding domain - Zinc finger domains binds to HREs
N-terminal domains (TAF1) transcriptional activation function - hormone independent
Prolactinoma: Excessive production of prolactin
Amenorrhea/oligomenorrhea w/ or w/o galactorrhea in women
Hypogonadism in men

Other causes of increased prolactin - pregnancy, hypothyroidism, breast or chest wall disease
Cushing's disease vs. Cushing's syndrome: Disease - excess production of glucocortcoids due to increased ACTH from the AP
Syndrome - any excess of glucorticoids from any source
Cushing's: Thinning of the skin
Easy bruiseability
Proximal muscle weakness
Mood changes

Testing - urinary free cortisol, DST, ACTH, CRH
Tx - TS resection, radiation, inhibitors of synthesis
Ectopic ACTH: Usually a fairly aggressive tumor
Most commonly an Oat's cell carcinoma of the lung, but many others
Diseases of the pituitary: Iatrogenic
Immunologic
Genetic, hypophysitis, surgery
Injury
Infiltrative - HX, sarcoidosis, hemochromatosis
Sheehan's
Infectious - TB, fungal, treponemal
SIADH: Dilutional hyponatremia with high urinary sodium
Small cell lung carcinoma
Intrauterine growth: Mean birth length - 50 cm
Mean birth weight - 3.5 kg
Independent of GH
IGF-2 thought to play a role
High insulin -> increased BW
Growth plate: Proliferation (germinal) zone
Flattened cell zone
Hypertrophic cell zone
BMI: BMI > 85% = obesity
BMI = weight(kg)/height(m^2)
High BMI associated with CV and DM risk and advanced bone age/precocious puberty
ACTH (Cortrosyn) stimulation test: Measures the ability of the adrenal cortex to respond to ACTH by producing cortisol appropriately
Normal infancy growth: Growth rate - 3-5 inches/year
Rate declines from neonatal period
Pattern/velocity determined by 36 months of age
Neonatal period growth (birth - 12 months): Normal rate - 9-11 inches/year
Rapid, highly variable rate
Childhood (3 years to puberty): Normal rate - 2-2.5 inches/year
Linear growth stabilizes
Changes in growth velocity indicates potential growth or health disorder
Adolescence: Growth rate is rapid and highly variable - increased production of adrenal and gonadal hormones
Onset of pubertal growth spurt - often preceded by measurable decline in growth rate
Average age in girls - 10
Average age in boys - 12.5
Late adolescence/early adulthood: Growth rate declines markedly after puberty
Bone growth ceases
Epiphyseal plates fuse
Height is stable
Calculated midparental height: Average +/- 2.5
Girls = (FH+MH)/2 - 2.5
Boys = (FH+MH)/2 + 2.5
Target height = Midparental height +/- 4 inches
Clues to recognizing growth failure: Height >2-2.5 SD below mean
Abnormal growth rate for age
-<3 years - <7 cm
-3-puberty - <4.5-5 cm
-during puberty - <6 cm
Height crossing 2 centiles after 3 years
Obese short child
Puberty w/o growth spurt
Extremely delayed bone age
Bone age: BA (years) measures growth potential
Estimated from x-ray of LT hand and wrist - correlate well with tibial growth plate
Males grow until BA = 16
Females grow until BA = 14
BA>CA -> less time to grow
BA<CA -> more time to grow
Short stature normal variants: Genetic short stature - r/o GH deficiency
-Final height short but appropriate for FH
-HA<BA=CA
Constitutional delay - males >>>> females
Endocrine causes of short stature: Primary hypothyroidism
Glucocorticoid excess
Isolated GH deficiency
Hypopituitarism
GH resistance
Biologically inactive GH
IGF-1 deficiency
Hypercortisolism - abnormal growth: Decreased secretion of GH
Counteracts local effects of GH, IGF-1
Increases somatostatin tone
Congenital GH deficiency: Normal birth weight and height
Midline defects
Often associated with other pituitary deficits
Statural growth decelerates while ponderal growth continues
GH deficiency: phenotype: Truncal obesity
Face appears younger than CA
Crowding of facial features to the center of the face (maxillary hypoplasia)
Small genitalia in boys
GH provocative tests: Needed since GH is mainly secreted at night
Insulin hypoglycemia, arginine, L-dopa, clonidine, GHRH
GH peak <10ng/ml is indicative of GHD
Low IGF-1 may reflect GH def.
May not reflect physiologic GH production during sleep
GH Rx: rDNA GH
Injected SC to optimize IGF-1
SE - increased ICP, allergic skin reaction, slipped capital femoral epiphysis, scoliosis
Iodide uptake: Energy requiring
Inhibited by hypoxia, CN, 2,4-DNP
Competitively inhibited by monovalent ions of the same size (thiocyanate, perchlorate)
Thioureas (PTU) inhibit iodination
Controlled by TSH - cAMP dependent kinase
Deiodination: Dehalogenase
Involves NADP
TRH pathway: Arcuate nucleus and median eminence secrete
Acts on thyrotrophs of AP
Gprotein -> PLC -> DAG, IP3
Thyoid hormone transport: Thyroid binding globulin TBG
Transthyretin TBP A
Albumin
Free hormone - T4 (0.03%), T3 (0.3%)
Estrogen - increased TBG
Testosterone, cortisol - decreased TBG
1/2 life of T3 = 1 day
1/2 life of T4 = 7 days
Type 1 5'-deiodinase: Kidney, liver, thyroid - high Km, depends on selenium, stress results in decreased type 1 activity, inhibited by PTU and propanolol, low in geriatric patients
Type 2 5'-deiodinase: Brain and pituitary
Low Km
High levels of serum T4 reduces type 2 enzyme
Increased in conditions of hypothyroidism
Type 3 5'-deiodinase: Placenta, glial cells, fetal liver
Inactivates T4 and T3 by conversion to rT3
Elevated in hyperthyroidism and decreased in hypothyroidism
Thyroid hormone action: Increase BMR
Necessary for normal fetal neonatal brain development
Stimulate protein synthesis but also breakdown
Stimulate lipogenesis but are also lipolytic
Increased HSL activity
Increased LPL activity
SNS-like actions - increased receptors and affinity
Inhibits fibroblast function
Protein levels affected by thyroid hormone: Through THR, RAR, TRE
Na-K pump
Gluconeogenic enzymes
Respiratory enzymes
Myosin heavy chain
Beta adrenergic receptors
Many others
Hormones secreted by the thyroid gland: Follicular cells - T4, T3, rT3
Parafollicular C cells - calcitonin
TSH: Half life of 50-60 minutes
Circulates unbound
Normal range 0.5-5.0
Thyroid hormones in blood: Total serum T4 - 5-12 ug/dL
Total serum T3 - 95-190 ng/dL
Free thyroxine index (FT4I): Total T4 x T4RU
Normal resin T4 uptake is 25-35%
High resin uptake = high T4 or low TBG
Low resin uptake = low T4 or high TBG
Acute thyroiditis: Infection - associated with malnutrition, trauma to neck, IS pts. - pyogenic organisms, fungi, TB, syphilis, PC (HIV)
Radiation induced
Subacute thyroiditis (Granulomatous or De Quervain's): Key - painful thyroid
Viral etiology?
F>M
Hyper -> hypo -> euthyroid
Subacute painless thyroiditis: High levels of thyroid hormone
Anti-thyroid Abs present
Likely autoimmune in nature
Subacute post-partum thyroiditis: Occurs within 6 months after childbirth
Overactive immune system
Chronic autoimmune thyroiditis: Most common form of thyroiditis
Atrophic form - idiopathic
Goitrous form - Hashimoto's
F>M peak at 30-50
Anti-microsomal, anti-TPO
Also TSH blocking Abs
Hurthle cells - large, eosinophilic epithelial cells
Lymphoma rare complication
Riedel's struma: Invasive fibrous thyroiditis
Rare
Unknown etiology
"Woody thyroid" - extensive fibrosis extending into adjacent tissue
Major symptoms are from tracheal compression
Goiter: Enlargement of thyroid
Normal weight - 15-35 grams
Iodine deficiency, goitrogens in diet, Hashimoto's, SAT, neoplasms, congenital defects, resistance to hormone
Thyrotoxicosis: Graves disease
Toxic multinodular goiter
Toxic adenoma
Thyroiditis
Iatrogenic or factitious
Carcinoma
Pituitary, trophoblastic tumors (hCG has intrinsic TSH activity)
Ectopic hormone - struma ovarii
Graves disease: MCC of hyperthyroidism
F>>M
TSH stimulating Abs
Exophthalmos - deposition of GAG in extraocular muscles leading to proptosis
Pretibial myxedema - accumulation of GAG
Thinning of lateral edge of the eyebrows
Hypothyroidism: Cretinism - birth
Myxedema - late childhood or adulthood
Primary - TSH elevated
Secondary - TSH low
Benign thyroid tumors: Usually single, complete fibrous capsule, adjacent tissue normal
Adenomas - almost always follicular
Teratomas - rare usually children
Therapeutic indications for anti-thyroidal agents: Graves' disease
Thyroid storm
Pre-operatively for thyroidectomy
Iodine induced thyrotoxicosis
Propanolol in thyroid disease: Adjunct in hyperthyroidism
Block adrenergic effects
In high doses can also inhibit T4 to T3 conversion
Competitive anions of iodide: Thiocyanate - toxic
Perchlorate - may cause fatal aplastic anemia
Fluoroborate
Thionamides: PTU and methimazole
Inhibit peroxidases and prevent oxidation of iodide
Takes a few days to weeks to see effect
Cross the placenta - less risk with PTU
Can be found in breast milk
SE - agranulocytosis, urticaria, arthralgia
Propylthiouracil (PTU): Also interferes with peripheral 5'-deiodinase conversion of T4 to T3 in addition to inhibiting iodination
Drug of chioce in thyroid storm
Methimazole: Longer acting/more potent than PTU
Iodine (I27 - non-RA): Paradoxical inhibitor of formation and secretion of thyroid hormone in high doses
Cause goiter and hypothyroidism in high concentrations
Effect is prompt, but short lived
Can decrease vascularity pre-op
Can be used to reduce radioactive iodine uptake
SE - angioedema, hemorrhages, serum sickness, brassy taste, oral burning, enlarged glands
Radioactive Iodide (I31): Half life 8 days
Beta emissions act almost exclusively on the follicular cells
Treatment of choice for hyperthyroidism and carcinoma of thyroid
Symptoms abate over months
Delayed hypothyroidism
CI in pregnancy
Diagnostic uses
Thyroid replacement therapy: Levothyroxine (T4) - drug of choice - incremental dosing
Liothyronine (T3) - rapid onset
Liotrix - 4:1 T4:T3
Aggressive therapy in cretinism and myxedema coma
Drug interactions of thyroid hormones: Competition for binding sites
Thyroxine binding increased
Drugs containing iodine
Hyperreactivity
Cholestyramine - inhibits absorption
Increased clearance of digoxin
Oral anticoagulant effects
Insulin less effective in hyperthyroidism
Glucocorticoids reduce peripheral deiodination and thyroid hormone activity
Anterior pituitary blood supply: Superior hypophyseal artery
Just proximal to carotid entrance into cavernous sinus
Posterior pituitary blood supply: Inferior hypophyseal artery
Branch of meningohypophyseal trunk of ICA in cavernous sinus
Complications of pituitary surgery: Microadenoma >60% 5 year
Macroadenoma <50% 5 year
Diabetes insipidus
CSF leak
Pan-hypopituitarism
Carotid artery injury
Visual loss
Death
Symptoms of hyperthyroidism DDx: Cardiomyopathy
Illicit drug use
GI disorder causing malabsorption
Hyperthyroidism
TSH or TSH-like thyrotoxicosis: Trophoblastic tumors (high levels of hCG)
Pituitary TSH
TRH secreting tumors
Apathetic thyrotoxicosis: Elderly patients with oligosymptomatic or atypical features of hyperthyroidism
Lack of eye findings or even ptosis
Variable cardiac features
Weight loss is the most reliable feature
Metabolic functions of calcium: Cellular adhesion
2nd messenger
Enzymatic activity
Neurotransmission
Fertility
Muscle contraction
Platelet aggregation
Blood coagulation
Compounds that complex calcium: Phytic acid (cereal)
Fatty acids (fal malabsorption)
Oxalic acid (rhubarb)
Osteomalacia: Rickets
Caused by deficiency of Ca2+
Due to lack of vitamin D in the diet or insufficient production in the skin (lack of sunlight)
Phosphate function: Buffering - in. and ex.
Energy metabolism
Membranes
Nucleic acids
Phos./Dephos.
Signal molecules
Serum calcium: 9-11 mg/dL
Low - convulsions (tetany)
High - neurologic damage and soft tissue calcifications
Parathyroid hormone: preproPTH -> proPTH -> PTH
N-terminal 33-36 contain biologic activity
Made in chief cells
Secretion triggered by low plasma Ca2+ - Ca sensor Gq
Action on the kidney - increases calcium reabsorption and phosphate excretion
Increases calcitriol production
Increases bone resorption - indirect via effect on osteoblasts which then stimulate osteoclasts
Calcitriol: Vitamin D obtained from the diet but also in the skin
7-DHC -> CCFol -> 25-OHD3 -> 1,25-DiOHD3
Skin -> liver -> kidney (proximal tubule)
Calcitriol action on the gut is to increase synthesis of a calcium binding protein and to increase phosphate absorption
Synergizes with PTH to turn on bone resorption
Vitamin D stimulates all three steps of transcellular absorption of Ca2+ (duodenum)
Calcitonin: Promotes the laying down of calcium into bone and the inhibition of bone resorption via osteoclast receptors
Inhibits Ca+ reabsorption by the kidney
Made in parafollicular cells of thyroid gland
Secreted in response to high Ca2+
Hypoparathyroidism: Hypocalcemia
Hyperphosphatemia
Neuromuscular irritability
Cataracts
Dental abnormalities
Mental abnormalities
Calcifications
Pseudohypoparathyroidism: Type I - def. of Galpha s or abnormalities in the PTH receptors decreased cAMP response - short stature, round facies, short metacarpal and metatarsal bones
Type II - normal PTH induced cAMP but with blunted 2nd messenger response
Primary hyperparathyroidism: Hypercalcemia and hypophosphatemia
Adenomas - MCC - usually monoclonal
Hyperplasia - usually chief cell - MEN association
Carcinoma - uncommon
Secondary hyperparathyroidism: Hypocalcemia and hyperphosphatemia
CRF - MCC
Parathyroid glands become hyperplastic
Tertiary hyperparathyroidism: Parathyroid hyperplasia becomes autonomous
Hypercalcemia of malignancy: PTH-related hormone (PTHrP)
Non-parathyroid source
Squamous carcinoma of lung
Adenocarcinoma of kidney
Hepatocellular carcinoma
Metastasis
Metastatic calcification: Increased CaxP results in deposition of CaPO4
Kidney tubules
Stomach - ulcers
Pancreas
Lung alveoli
Skin, tendon, blood vessels
Calciphylaxis: CRF where localized areas of skin become necrotic secondary to associated vascular calcification
Responsive to parathyroidectomy
Osteitis fibrosa cystica: Osteoclastic resorption
Osteoblastic activity but little actual bone formation
Cortical erosions - phalanges
Cystic tumors - hemorrhage
May form cytic "tumors" - Brown tumor due to hemorrhage - these tumors fill in once hyperparathyroid is treated
Distinguish from giant cell
MEN I: Pituitary
Pancreatic islets
Parathyroid hyperplasia
MEN II: Parathyroid hyperplasia
Medullary thyroid carcinoma
Pheochromocytoma
MEN IIB or III: Medullary thyroid carcinoma
Pheochromocytoma
Mucosal neuromas
Hypercalcemic hormones - increase serum calcium: PTH
Calcitriol
Hypocalcemic hormone - decrease serum calcium: Calcitonin
Hypocalcemia: Ca2+ <7 mg/dL
Paresthesias
Muscle cramps
Tetany
Convulsions
May cause death due to laryngospasms
Hypercalcemia: Ca2+ >12 mg/dL
Lethargy, drowsiness, coma
Neuromuscular fatigue and weakness
HTN
Bradycardia
N&V, constipation
Nephropathy
Soft tissue calcification
X-linked hypophosphatemia rickets: Severe bone demineralization and hypophosphatemia due to impaired renal phosphate transport rather than a primary abnormality in vitamin D metabolism
Paget's disease: Chronic localized areas of bone destruction, coupled to accelerated bone repair
Single or multiple foci of disordered bone remodeling
Vitamin D: Oral and IV
Bile is essential for absorption
Circulates in plasma bound to vitamin D binding protiein
Major circulating form is 25(OH)D3
Clinical uses of calcitriol: Fast acting
Hypoparathyroidism
Pseudohypoparathyroidism
Renal osteodystrophy
Vitamin D dependent rickets
X-linked HP rickets
In patients on phenytoin when there is inhibition of 1-hydroxylation
Vitamin D analogues - DHT: Does not require 1-hydroxylation
Faster onset and greater effect on mobilization of bone salts
Vitamin D analogues - doxercalciferol , paricalcitol: Used to suppress the secondary hyperparathyroidism seen in CRF
Able to suppress PTH secretion w/o an excessive hypercalcemic response
Clinical uses of PTH: Diagnostic drug - confirm the diagnosis of pseudohypoparathyroidism
Patient will fail to show an increase in serum calcium concentration after PTH injection and will also fail to show an increased excretion of phosphate and cAMP in the urine
Teriparatide - osteoporosis
Clinical uses of calcitonin: Half life in plasma - 40 min
Paget's disease
Hypercalcemia of various cause
Post-menopausal osteoporosis
SE - urticaria, swelling, GI upset
Resistance to chronic use is common
Ab production to calcitonin occurs with chronic use
Bisphosphonates: Structurally related to pyrophosphate
Anti-bone resorptive
"PIE-RATZ"
Paget's - TAPER
Hypercalcemia of malignancy - PZ
Osteoporosis - AIR
SE - esophagitis, E-osteomalacia, Z-renal
Calcium salts: Carbonate, lactate, gluconate, phosphate - oral
Gluconate, chloride, gluceptate - IV
CaCO3 use in long term prophylaxis of osteoporosis
Calcium gluconate (IV) treatment of choice for hypocalcemic tetany
Sevalamer: Calcium and aluminum free phosphate binding resin
Used in hyperphosphatemia (CRF)
Phosphate salts: Used in treatment of hypercalcemia and forms of hypophosphatemia
Treatment of hypercalcemia: Glucocortioid - particularly due to sarcoidosis
Calcitonin
Bisphosphonates
Mithramycin
Gallium nitrate
IV furosemide - acute calciuresis - use w/IV saline
EDTA - chelation (nephrotoxic)
Inorganic phosphates
Treatment of osteoporosis: HRT
Bisphosphonates
Ralofoxine - SERM
Teriparatide
Calcitonin
Vitamin D/calcium
Drugs accelerating metabolism of 25(OH)D: Phenytoin
Phenobarbital
Carbamazepine
Rifampin
Inhibitors of bone mineralization: Aluminum
Fluoride
Bisphosphonates
Phosphate disorders
Osteomalacia - causes: Vitamin D metabolism disorders
Cirrhosis and other chronic hepatic disorders
Renal disease
Vitamin D dependent Type I
Anticonvulsants
Rapid acting insulins: SLAP-R
Semilente
Lispro
Aspart
Powdered
Regular
ONSET - most <15 minutes; R+S -> 0.5-1.5 hours
DURATION - various 3-10 hours
Intermediate acting insulins: NPH
Lente
DURATION - 18-24 hours
Long acting insulins: Ultralente - >36 hours
Glargine - 24 hours - *Glargine cannot be mixed due to acid pH
Zinc and protamine: Stabilizing agents
Prolong the absorption of insulin
Increased Zn => absorption rate decreases => duration of activity increases
Lispro Aspart: Modified human insulin solution - rapid acting - shorter duration
Advantages - Improves quality of life due to flexible injection times, less frequent hypoglycemic reactions, can be used in pumps
Glargine insulin: Long lasting basal insulin levels - need rapid acting insulin at meal times
Powdered human insulin: Rapidly absorbed
Hypoglycemia
Not for anyone <18
May be adjuvant in type I or II
Adverse reaction of insulin preparations: Hypoglycemia
Immune/allergic response
Atrophy of fat at injection site
Hypokalemia
Powdered form - coughing, SOB, dry mouth, sore throat
Dosing of insulin: Morning glycosuria - need fast acting insulin in AM
Night glycosuria - need long acting insulin
Insulin resistant - much higher doses
Symlin (pramlintide acetate): Synthetic analog of amylin
Achieve lower blood glucose after meals
Helps suppress glucagon secretion
AE - severe hypoglycemia, nausea
Substances that may increase the blood glucose control lowering effect of insulin: ACE inhibitors
Disopyramide
Fibrates
Fluoxetine
MAOI
Propoxyphene
Salicylates
Somatostatin analog (octreotide)
Sulfonamide antibiotics
Substances that may decrease the blood glucose control lowering effect of insulin: Corticosteroids
Niacin
Danazol
Diuretics
Sympathomimetics
Isoniazid
Phenothiazine derivatives
Somatropin (GH analog)
TH
Estrogens
Progestins
Sulfonylureas: Mechanism of action - blocks ATP sensitive K+ channel -> insulin release; inhibit glucose release from liver; enhance IR number
CATT - 1st generation
GGG - 2nd generation
2nd more potent
Problems with 1st generation - hyponatremia, prolonged hypoglycemia, alcohol flush, interactions
Advantages of 2nd generation - high potency, free water diuresis, inactive metabolites, non-ionic binding, no alcohol flushing
Cardiovascular effects and antidiuretic effect
Adverse effects of sulfonylureas: Hypoglycemia
Leukopenia, hemolytic anemia
Rashes, photosensitivity
Nausea, vomiting, jaundice
CI in pregnancy
Drugs impairing sulfonylureas: Corticosteroids
Thiazide and furosemide diuretics
Oral contraceptives
Drugs which potentiate hypoglycemic therapy: Phenylbutazone and clofibrate
Alcohol
Aspirin
Beta blockers
Meglitinides: Repaglinide, glyburide, glipizide, glimepiride: Oral hypoglycemic agent
Binding site on ATP sensitive K+ channel - different site from sulfonylureas
Rapid onset, short duration
Insulin secretion response mainly confined to prandial glucose load
Synergistic with metformin
Low rate of hypoglycemia
CI - hypersensitivity, Type I DM, DKA, liver function decline, serious CV events
Nateglinide: starlix: D-phenylalanine class of hypoglycemic agents
Inhibits K+ channel
Fast on fast off
Low incidence of hypoglycemia
Can be combined w/metformin or alpha-glucosidase inhibitors
Less likely to causes CV effects
CI - pregnancy, lactation, type I DM, DKA
Metformin: Potentiates insulin action
Does not act on beta cells
Anti-hyperglycemic not hypoglycemic
Favorably affects lipids
Does not cause hyperinsulinemia
Inhibits intestinal absorption of AA's
Anti-inflammatory actions
Renal effects - decrease acid excretion
Increases blood pressure
Toxicity - lactic acidosis, ketonuria, GI effects, acute pancreatitis
Thiazolidinediones - rosiglitazone, pioglitazone: Act only in the presence of insulin and enhance insulin target response in target tissues thereby reducing insulin resistance
Binds to and activates PPAR-gamma - gene transcription
Increases GLUT1 synthesis, increases glucose uptake
Increases differentiation of pre-adipocyte to adipocyte
Possible loss of contraception
CI - pregnancy, breast feeding, active liver disease
AE - hypoglycemia, edema, anemia, ovulation, weight gain
Hypoglycemic glitazars: Target the alpha and gamma families of PPAR
PPAR-alpha - reductions in plasma TG level, increased HDL
PPAR-gamma - decreased plasma glucose
Alpha glucosidase inhibitors: Delay and reduce uptake of carbohydrates across the intestine
Competitive inhibition of the enzymatic digestion of carbohydrates in the intestinal lumen
Acarbose - non-absorbable
-SE - flatulence, pain, diarrhea
Glyset - absorbable
-CI in kidney dysfunction
Incretin mimetics: Exenatide
Similar sequence to GLP-1
Stimulates insulin secretion, inhibits glucagon secretion and slows gastric emptying and increases weight loss
Increases cAMP in the beta cell -> increases insulin
Reduces HbA1C
Glucagon: Emergency treatment of hypoglycemia
Relaxes intestinal smooth muscle; radiography
(+) inotropy, can be used in propanolol poisoning
Somatostatin: Lowers blood glucose in type I DM
May suppress glucagon secretion
Vanadate: Insulin like activity in vivo
Phosphatase inhibitor that augments insulin receptor activation
Alloxan: Hyperglycemic agent
Inhibits glucose interaction with beta cell - produces diabetic state
Diazoxide: Non-diuretic thiazide suppresses insulin secretion and peripheral utilization of glucose
Streptozocin: Selectively destroys beta cells by alkylating bases of DNA and generating free radicals
Effects of sorbitol accumulation: Osmotic swelling
Decreased nerve conduction velocity
Cataract formation
Neuropathy
Sorbinil/tolrestat: Inhibits aldose reductase
Improves Na/K ATPase activity
Prevents cataracts
Myo-inositol: Appears to relieve some of the pathologies of DM - neuropathy
Renal effects of mineralocorticoids: Rapidly stimulate expression of sgk - enhanced Na+ channel surface expression
Promotes resorption of NaCl and secretion of K+ in cortical collecting tubule
Increases number of NaCl cotransporters in the distal tubule
Increased H+ excretion
Aldosterone escape phenomenon: Release of natriuretic factor from the hypothalamus
Increase in glomerular filtration due to ANP
Suppressed RAAS due to rise in systemic BP, renal perfusion pressure, and sodium content in the macula densa
K+ excretion continues
Mineralocorticoid receptor: Roughly equal affinities for cortisol and aldosterone
Renal concentration of cortisol is 1,000 fold higher than aldosterone
11-beta-HSDH2 converts cortisol to cortisone
Cardiovascular effects of aldosterone: Upregulates AT1 receptors - blocked by spironolactone and losartan
Cardiac myocytes, endothelial cells, and VSMC's contain high affinity MR's - 11-beta-HSDH2 present
In patients with CHF, spironolactone may improve outcome by reducing levels of procollagen
11-beta hydroxylase form of CAH: More common in Jews of Moroccan ancestors
AR - chromosome 8
Virilization w/HTN
Decreased cortisol levels, increased androgens, increased 11-deoxycortisol
17-alpha hydroxylase form of CAH: AR - chromosome 10
Cortisol and androgen are decreased
HTN
DOC and corticosterone will be increased
HTN due to glucocorticoids: Increases the number of alpha-adrenergic, AII, and ADH receptors
Increase AII production and upregulate ACE expression
Increase GFR
Downregulates the expression of Na-Ca exchanger - increased cytosolic calcium and vasoconstriction
Cushing's syndrome: Thinning of the skin
Easy bruiseability
Muscular weakness (proximal)
Mood changes
HTN due to pheochromocytoma: About 20% familial
Monitor urinary catecholamine products - metanephrine
Histone interaction w/hormone response: (+) hormone -> coactivator complex containing HAT
(-) hormone -> corepressors containing histone deacetylase
GR-mediated transcriptional modulation: Antagonizes AP-1, STATs, CREB, NF-kB
Inhibits NF-kB by increasing IkB
Target genes for GCs: Beta-adrenergic receptor
IkB - sequesters NF-kB
Increased mRNA 1/2 life - collagenase
Decreased mRNA 1/2 life - COX-2
Decreased gene transcription - TNF-a, GM-CSF, iNOS, COX-2, adhesion molecules
Hypothalamus-anterior pituitary relationship: Portal blood supply from the hypothalamic veins to the organ capillaries of the anterior pituitary - regulates hormone release
Removal of the pituitary: Atrophy of gonads
Atrophy of adrenal cortex
Atrophy of thyroid
Interruption of the ovarian cycle
Decreased ability to respond to stress
Inhibition of growth and development in young animals
3 groups of anterior pituitary hormones: Large glycoproteins - TSH, LH, FSH
Large straight-chain polypeptides - GH, prolactin
Small peptides - ACTH, a-MSH, b-lipotropin, b-endorphin
Inhibin: Sertolli cell is the major source in the testis
Ovarian granulosa cell is the major source in the female
Inhibits FSH release
Hypersecretion of GH: Acidophilic or chromophobic adenoma
Prolactin: Anti-reproductive or anti-gonadal effects
Prolactin can suppress LH and lead to anovulation
TRH can stimulate prolactin secretion
Prolactinoma - chromophobe
ACTH: Increases the rate of cholesterol side-chain cleavage - the rate-limiting step
Direct lipotrophic effect on adipose tissue
Diurnal release rhythm
Common characteristics of endocrine organs: Possess no ducts
Secrete directly into vascular system
Rich blood supply - fenestrated endothelium
Reacts to suppression or stimulation
Steroid secreting cells: Mesoderm
Abundant SER
Large mitochondria w/extensive cristae
Lipid droplets with free cholesterol, esters, no limiting membrane
Enzymes for steps are present in distinct organelles
No stored hormone
Adrenal cortex - organization: ZG - cords in ball shape, few lipid droplets, shelf-like cristae
ZF - straight cords, tubular-vesicular cristae
ZR - branching, few lipid droplets, tubular-vesicular
Adrenal development: Fetal (80%)/Permanent (20%) -> after birth permanent cortex 100%
Testis, Leydig cells: Light staining vacuolated cytoplasm
Contain lipochrome pigment granules, crystals of Reinke
Ovary: Theca interna cells - respond to LH by producing ASDione and testosterone
Granulosa cells - synthesize aromatase in response to FSH (can make estrogen)
Progesterone produced by corpus luteum
JGA: Modified myoepithelial cells in wall of afferent arteriole and a few in efferent
Cytoplasmic granules with PAS or Bowie's ethyl violet
Secretes renin
Angiotensin II: Potent vasoconstrictor
Simulates aldosterone
Polypeptide, AA organs: RER, small golgi
Hormone stored
Role of microtubules
Anterior pituitary - acidophil: GH
Prolactin
Anterior pituitary - basophil: TSH
FSH
LH
ACTH
Pars intermedia: Produces MSH
Herring bodies: Local accumulations of neurosecretory material in axoplasm of fibers of hypothalamo-hypophyseal tract
Contains hormones produced in hypothalamic nuclei
Neurophysin - large carrier protein to which oxytocin and ADH are bound
Islets of Langerhans - structure: Spheroid structures
Pale staining cells
More numerous in tail and body than head
Alpha cell - insoluble in alcohol, periphery, highly opaque granules
Beta cell - soluble in alcohol, interior of islet, less electron opaque, more numerous, alloxan injures
Delta cell - Masson's triple stain, few
F cell - pancreatic polypeptide
Parathyroid glands - structure: Chief cells - glycogen
Oxyphil cells - larger cells
Adrenal medulla - structure: E secretory granules - homogeneous, less electron opaque
NE - secretory granules - very electron opaque
Pineal gland - structure: Pinealocytes - large nuclei, SER
Astroglial cells - IFs
Corpora arenacea - brain sand
Post-ganglionic SNS
Serotonin/melatonin
Arginine vasotocin - anti-gonadotroph
-Pineal tumor - precocious puberty
ADH control: Controlled by plasma osmolality
High osmolality increased ADH
Increased in severe blood loss, nicotine, saline loading, dehydation
Decreased by ethanol, emotional stress, cold
Osmoreceptors- hypothalamus Stretch receptors - heart, aorta are inhibitory
Actions of ADH: Increased permeability of distal nephron
High doses - vasoconstriction
Stimulates renal mesangial cell contraction
Inhibits renin
Stimulates ACTH secretion
Increase in plasma ADH is dramatic above osmolality of 290
Suspect SIADH: Low serum Na+ with high urine Na+
Primary congenital adenohypophysis malformation: Complete absence
Ectopia - improper migration of Rathke's pouch
Secondary congenital malformation of adenohypophysis: Anencephaly
Holoprosencephaly - affects olfactory, impaired midline cleavage of forebrain, midline dysplasia of face
Kallmann syndrome - X-linked - hypogonadotropic hypogonadism
Cleft lip and palate - selective GH deficiency
Hereditary dyfunction of adenohypophysis: Isolated GH deficiency - AD
Panhypopituitary dwarfism - sporadic - deficiency of GH and others (most frequently gonadotrophins)
Sheehan's syndrome: Severe anterior pituitary insufficiency following severe intrapartum or post-partum hemorrhage
Chronic inflammatory disease affecting the AP: TB, sarcoid, syphilis, rarely mycotic
Lymphoid hypophysitis: Autoimmune, rare
Immunologic attack on prolactin cells
Following pregancy
Hunter-Hurler disease: AP - Foamy cells and distended due to accumulation of mucopolysaccharides
Hemochromatosis - AP: Iron deposited in AP as in other organs - AR
Hypogonadotropic hypogonadism is most common manifestation
Pituitary adenomas: Microadenoma - <1 cm
Macroadenoma - >1 cm
Optic nerve, chiasm compression - BTH
Hypopituitarism
Hyperprolactinemia
MEN I
Pituitary carcinoma - rare
In men - hypogonadism
Craniopharyngioma: Tumor of maldevelopmental origin - stratified squamous and ameloblastic epithelium
Epithelia displaced from oral cavity
Cause visual symptoms
Frequently calcify
Cystic containing turbid yellow fluid
Germinoma: Morphologically identical to seminomas
Usually involve posterior lobe and tuber cinereum and cause DI
Primary adrenal hyperplasia -influence on AP: Crooke's hyaline change occurs in ACTH producing cells
Empty Sella Syndrome: Diaphragm of the sella turcica has an opening much wider than necessary for passage of the pituitary stalk
Downward herniation of the subarachnoid space compressing the stalk and the gland
Secondary causes of elevated prolactin: Pregnancy
Hypothyroidism
Breast or chest wall disease
Suprasellar disease
Drugs - anti-psychotics
Acromegaly - clinical features: Slow proliferation of soft tissue and cartilage
Acral bone growth
Visceral and cutaneous growth
HTN and insulin resistance
HA
Acromegaly diagnosis: Basal fasting GH is elevated - >10
Failure of GH to suppress following glucose load
Elevated IGF-1
L-dopa suppresses GH (normal is increased GH)
Acromegaly - treatment: Surgery - larger = poorer outcome
Radiation - adjuvant, GH levels decline over years
Medical - octreotide (somatostatin), DA agonists
Cushing's syndrome diagnosis: Urinary free cortisol
DST - low and high dose
ACTH
CRH
Cushing's disease (pituitary) treatment: Trans-sphenoidal resection
Radiation may have fairly quick impact (contrast to GH)
Inhibitors of synthesis
Nelson's syndrome: Clinical appearance of an ACTH secreting tumor following bilateral adrenalectomy
Suppressive effect of cortisol is no longer present
Central causes of DI: Head trauma
Surgery
Mass effect on the hypothalamus by craniopharyngioma
Local growths
Tumors or infarctions causing edema
Diabetes insipidus - clinical and diagnosis: Polyuria
Polydipsia
Hypernatremia
Dilute urine
Use water deprivation with hourly monitoring of urine volume and osmolality
Response to AVP or DDAVP
Hypopituitarism - causes: Iatrogenic - surgery, radiation
Hypophysitis
Injury related
Histiocytosis X, sarcoidosis, hemochromatosis
Sheehan's syndrome
TB, fungal, treponemal
Hypopituitarism - testing: Serum cortisol +/- ACTH, CRH
Short loop testing - cosyntropin
Long loop testing - metyrapone, insulin hypoglycemia
Prolactin, FSH, LH, clomiphene, GnRH
TSH, T4, T3, TRH
GH - L-dopa test, arginine infusion test, insulin hypoglycemia
SIADH - causes and clincal picture: Bronchogenic carcinoma, other malignancies
CNS trauma, malignancy, infection, inflammation
Drugs

Euvolemic hyponatremia with dilute urine and normal thyroid and adrenal function
Diagnostic work up for suspected growth abnormality: History - pregnancy, general, growth, family
CBC
ESR
Electrolytes
Chemistry panel
T4
TSH
Bone age
Skull x-ray films
Chromosomal karyotyping
Anti-gliadin Ab
RBC folate and carotene
24 hour urinary cortisol
IGF-1
GH stimulation test
CT or MRI of the skull

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Number of cards 243