Endocrine - Physiology

Question 1

Insulin

• Synthesis
• Source

Answer 1

• Synthesis
  
  • Preproinsulin (synthesized in RER)
    
    • –>Ž cleavage of “presignal”
    • –>Ž proinsulin (stored in secretory granules)
    • –>Ž cleavage of proinsulin Ž
    • –> exocytosis of insulin and C-peptide equally.
  • Insulin and C-peptide are increased in insulinoma, whereas exogenous insulin lacks C-peptide.
• Source
  
  • Released from pancreatic β cells.

Question 2

Insulin (308)

• Function
  
  • Binds…
  • Anabolic effects of insulin:
  • Insulin…
  • Insulin-dependent glucose transporters:
  • Insulin-independent transporters:
  • Brain…

Answer 2

• Function
  
  • Binds insulin receptors (tyrosine kinase activity [1]), inducing glucose uptake (carrier-mediated transport) in insulin-dependent tissue [2] and gene transcription.
  • Anabolic effects of insulin:
    
    • Increased glucose transport in skeletal muscle and adipose tissue
    • Increased glycogen synthesis and storage
    • Increased triglyceride synthesis
    • Increased Na+ retention (kidneys)
    • Increased protein synthesis (muscles, proteins)
    • Increased cellular uptake of K+ and amino acids
    • Decreased glucagon release
  • Insulin moves glucose into cells.
    
    • ​Unlike glucose, insulin does not cross placenta.
  • Insulin-dependent glucose transporters:
    
    • GLUT-4: adipose tissue, skeletal muscle
  • Insulin-independent transporters:
    
    • GLUT-1: RBCs, brain, cornea
    • GLUT-5 (fructose): spermatocytes, GI tract
    • GLUT-2 (bidirectional): β islet cells, liver, kidney, small intestine
    • BRICK L (insulin-independent glucose uptake): Brain, RBCs, Intestine, Cornea, Kidney, Liver.
  • Brain utilizes glucose for metabolism normally and ketone bodies during starvation.
    
    • RBCs always utilize glucose because they lack mitochondria for aerobic metabolism.

Question 3

Insulin (308)

• Regulation
  
  • Glucose (general)
  • GH and β2-agonists
  • Glucose (mechanism)

Answer 3

• Regulation
  
  • Glucose is major regulator of insulin release.
  • GH (causes insulin resistance –> increased insulin release) and β2-agonists –>Ž increased insulin.
  • Glucose enters β cells [3]Ž
    
    • –> increased ATP generated from glucose metabolism [4] closes K+ channels [5] and depolarizes β cell membrane [6]
    • –> opens voltage-gated Ca2+ channels, resulting in Ca2+ influx [7] and stimulating insulin exocytosis [8].

Question 4

Glucagon

• Source
• Function
• Regulation

Answer 4

• Source
  
  • Made by α cells of pancreas.
• Function
  
  • Catabolic effects of glucagon:
    
    • ƒƒGlycogenolysis, gluconeogenesis
    • Lipolysis and ketone production
• Regulation
  
  • Secreted in response to hypoglycemia.
  • Inhibited by insulin, hyperglycemia, and somatostatin.

Question 5

Hypothalamic-pituitary hormones

• For each
  
  • Function
  • Clinical notes
• CRH
• Dopamine
• GnRH
• Prolactin
• Somatostatin
• TRH

Answer 5

• CRH 
  
  • Function: increases ACTH, MSH, β-endorphin 
  • Clinical notes: Decreased in chronic exogenous steroid use
• Dopamine 
  
  • Function: decreases prolactin
  • Clinical notes: Dopamine antagonists (e.g., antipsychotics) can cause galactorrhea
• GnRH 
  
  • Function: increases FSH, LH
  • Clinical notes: Regulated by prolactin
    
    • Tonic GnRH suppresses HPA axis
    • Pulsatile GnRH leads to puberty, fertility
• Prolactin 
  
  • Function: decreases GnRH
  • Clinical notes: Pituitary prolactinoma –>Ž amenorrhea, osteoporosis
• Somatostatin 
  
  • Function: decreases GH, TSH
  • Clinical notes: Analogs used to treat acromegaly
• TRH 
  
  • Function: increases TSH, prolactin
  • Clinical notes: N/A

Question 6

Prolactin

• Source
• Function
• Regulation

Answer 6

• Source
  
  • Secreted mainly by anterior pituitary.
• 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 decreased libido.
• Regulation
  
  • Prolactin secretion from anterior pituitary is tonically inhibited by dopamine from hypothalamus.
    
    • Prolactin in turn inhibits its own secretion by increasing dopamine synthesis and secretion from hypothalamus.
    • TRH increases prolactin secretion.
  • Dopamine agonists (bromocriptine) inhibit prolactin secretion and can be used in treatment of prolactinoma.
  • Dopamine antagonists (most antipsychotics) and estrogens (OCPs, pregnancy) stimulate prolactin secretion.

Question 7

Growth hormone (somatotropin)

• Source
• Function
• Regulation

Answer 7

• Source
  
  • Secreted mainly by anterior pituitary.
• Function
  
  • Stimulates linear growth and muscle mass through IGF-1/somatomedin secretion.
  • Increases insulin resistance (diabetogenic).
• Regulation
  
  • Released in pulses in response to growth hormone–releasing hormone (GHRH).
    
    • Secretion increases during exercise and sleep.
    • Secretion inhibited by glucose and somatostatin.
  • Excess secretion of GH (e.g., pituitary adenoma) may cause acromegaly (adults) or gigantism (children).

Question 8

Antidiuretic hormone

• Source
• Function
• Regulation

Answer 8

• Source
  
  • Synthesized in hypothalamus (supraoptic nuclei), released by posterior pituitary.
• Function
  
  • Regulates serum osmolarity (V2-receptors) and blood pressure (V1-receptors).
    
    • Primary function is serum osmolarity regulation (ADH decreases serum osmolarity, increases urine osmolarity) via regulation of aquaporin channel transcription in principal cells of renal collecting duct.
  • ADH level is decreased in central diabetes insipidus (DI), normal or increased in nephrogenic DI and 1° polydipsia.
  • Nephrogenic DI can be caused by mutation in V2-receptor.
  • Desmopressin (ADH analog) = treatment for central DI.
• Regulation
  
  • Osmoreceptors in hypothalamus (1°)
  • Hypovolemia (2°).

Question 9

Adrenal steroids and congenital adrenal hyperplasias (312)

• 17α-hydroxylase
  
  • Minearlocorticoids (increased/decreased)
  • Cortisol (increased/decreased)
  • Sex hormones (increased/decreased)
  • Labs
  • Presentation

Answer 9

• 17α-hydroxylasea   
  
  • Minearlocorticoids: increased
  • Cortisol: decreased
  • Sex hormones: decreased
  • Labs:
    
    • Hypertension
    • Hypokalemia
    • Decreased DHT
  • Presentation:
    
    • XY: pseudo-hermaphroditism (ambiguous genitalia, undescended testes)
    • XX: lack secondary sexual development

Question 10

Adrenal steroids and congenital adrenal hyperplasias (312)

• 21-hydroxylase
  
  • Minearlocorticoids (increased/decreased)
  • Cortisol (increased/decreased)
  • Sex hormones (increased/decreased)
  • Labs
  • Presentation

Answer 10

• 21-hydroxylasea   
  
  • Minearlocorticoids: decreased
  • Cortisol: decreased
  • Sex hormones: increased
  • Labs:
    
    • Hypotension
    • Hyperkalemia
    • Increased renin activity
    • Increased 17-hydroxy-progesterone
  • Presentation:
    
    • Most common
    • Presents in infancy (salt wasting) or childhood (precocious puberty)
    • XX: virilization

Question 11

Adrenal steroids and congenital adrenal hyperplasias (312)

• 11β-hydroxylase
  
  • Minearlocorticoids (increased/decreased)
  • Cortisol (increased/decreased)
  • Sex hormones (increased/decreased)
  • Labs
  • Presentation
• All congenital adrenal enzyme deficiencies are characterized by…

Answer 11

• 11β-hydroxylasea 
  
  • Minearlocorticoids:
    
    • Decreased aldosterone
    • Increased 11-deoxycorticosterone (results in increased BP)
  • Cortisol: decreased
  • Sex hormones: increased
  • Labs:
    
    • Hypertension (low-renin)
  • Presentation:
    
    • XX: virilization
• All congenital adrenal enzyme deficiencies are characterized by an enlargement of both adrenal glands due to increased ACTH stimulation (due to decreased cortisol).

Question 12

Cortisol

• Source
• Function
• Regulation

Answer 12

• Source
  
  • Adrenal zona fasciculata.
  • Bound to corticosteroid-binding globulin.
• Function
  
  •  Cortisol is a BIG FIB.
    
    • Increased Blood pressure (upregulates α1-receptors on arterioles Ž–> increased sensitivity to norepinephrine and epinephrine)
    • Increased Insulin resistance (diabetogenic)
    • Increased Gluconeogenesis, lipolysis, and proteolysis
    • Decreased Fibroblast activity (causes striae)
    • Decreased Inflammatory and Immune responses:
      
      • Inhibits production of leukotrienes and prostaglandins
      • Inhibits leukocyte adhesion –>Ž neutrophilia
      • Blocks histamine release from mast cells
      • Reduces eosinophils
      • Blocks IL-2 production
    • Decreased Bone formation (decreased osteoblast activity)
  • Exogenous corticosteroids can cause reactivation of TB and candidiasis (blocked IL-2 production).
• Regulation
  
  • CRH (hypothalamus) stimulates ACTH release (pituitary), causing cortisol production in adrenal zona fasciculata.
  • Excess cortisol decreases CRH, ACTH, and cortisol secretion.
  • Chronic stress induces prolonged secretion.

Question 13

PTH (314)

• Source
• Function
  
  • PTH
  • PTH-related peptide
• Regulation

Answer 13

• Source
  
  • Chief cells of parathyroid.
• Function
  
  • PTH = Phosphate Trashing Hormone.
    
    • Increased bone resorption of Ca2+ and PO₄^3-.
    • Increased kidney reabsorption of Ca2+ in distal convoluted tubule.
    • Decreased reabsorption of PO₄^3- in proximal convoluted tubule.
    • Increased 1,25-(OH)2 D3 (calcitriol) production by stimulating kidney 1α-hydroxylase.
    • PTH increases serum Ca2+, decreases serum (PO₄^3-), increases urine (PO₄^3-).
    • Increased production of macrophage colony-stimulating factor and RANK-L (receptor activator of NF-κB ligand).
      
      • RANK-L binds RANK on osteoblasts –>Ž osteoclast stimulation and increased Ca2+.
  • PTH-related peptide (PTHrP) functions like PTH and is commonly increased in malignancies (e.g., paraneoplastic syndrome).
• Regulation
  
  • Decreased serum Ca2+ Ž–> increased PTH secretion.
  • Decreased serum Mg2+ –>Ž increased PTH secretion.
  • Really decreased serum Mg2+ –>Ž decreased PTH secretion.
  • Common causes of decreased Mg2+ include diarrhea, aminoglycosides, diuretics, and alcohol abuse

Question 14

Calcium homeostasis

• Plasma Ca2+ exists in three forms:
• Increase in pH –>

Answer 14

• Plasma Ca2+ exists in three forms:
  
  • Ionized (~45%)
  • Bound to albumin (~40%)
  • Bound to anions (~15%)
• Increase in pH
  
  • –>Ž increased affinity of albumin (negative charge) to bind Ca2+
  • –> clinical manifestations of hypocalcemia (cramps, pain, paresthesias, carpopedal spasm).

Question 15

Vitamin D (cholecalciferol)

• Source
• Function
• Regulation
• Deficiency causes…
• 24,25-(OH)2 D3
• PTH vs. 1,25-(OH)2

Answer 15

• Source
  
  • D3 from sun exposure in skin.
  • D2 ingested from plants.
  • Both converted to 25-OH in liver and to 1,25-(OH)2 (active form) in kidney.
• Function
  
  • Increased absorption of dietary Ca2+ and PO₄^3-
  • Increased bone resorption –>Ž increased Ca2+ and PO₄^3-
• Regulation
  
  • Increased PTH, decreased [Ca2+], decreased PO₄^3- cause increased 1,25-(OH)2 production.
  • 1,25-(OH)2 feedback inhibits its own production.
• Deficiency causes rickets in kids and osteomalacia in adults.
  
  • Caused by malabsorption, decreased sunlight, poor diet, chronic kidney failure.
• 24,25-(OH)2 D3 is an inactive form of vitamin D.
• PTH vs. 1,25-(OH)2
  
  • PTH leads to increased Ca2+ reabsorption and decreased PO₄^3- reabsorption in the kidney
  • 1,25-(OH)2 leads to increased absorption of both Ca2+ and PO₄^3- in the gut.

Question 16

Calcitonin

• Source
• Function
• Regulation

Answer 16

• Source
  
  • Parafollicular cells (C cells) of thyroid.
• Function
  
  • Decreases bone resorption of Ca2+.
  • Calcitonin opposes actions of PTH.
    
    • Not important in normal Ca2+ homeostasis.
  • Calcitonin tones down Ca2+ levels.
• Regulation
  
  • Increased serum Ca2+ causes calcitonin secretion.

Question 17

Signaling pathways of these endocrine hormones

• cAMP
• cGMP
• IP3
• Steroid receptor
• Intrinsic tyrosine kinase
• Receptor-associated tyrosine kinase

Answer 17

• cAMP
  
  • FLAT ChAMP GCG
  • FSH, LH, ACTH, TSH, CRH, hCG, ADH (V2-receptor), MSH, PTH, _G_HRH, _C_alcitonin, _G_lucagon
• cGMP
  
  • Think vasodilators
  • ANP, NO (EDRF)
• IP3
  
  • GOAT HAG
  • GnRH, Oxytocin, ADH (V1-receptor), TRH, Histamine (H1-receptor), Angiotensin II, Gastrin
• Steroid receptor
  
  • VETTT CAP
  • Vitamin D, Estrogen, Testosterone, T3/T4 Cortisol, Aldosterone, Progesterone
• Intrinsic tyrosine kinase
  
  • Think growth factors
  • Insulin, IGF-1, FGF, PDGF, EGF
    
    • MAP kinase pathway
• Receptor-associated tyrosine kinase
  
  • PIG, think acidophiles and cytokines
  • Prolactin, Immunomodulators (e.g., cytokines IL-2, IL-6, IL-8, IFN), GH
    
    • JAK/STAT pathway

Question 18

Signaling pathway of steroid hormones

• Steroid hormones
• Men vs. women
• OCPs, pregnancy

Answer 18

• Steroid hormones are lipophilic and therefore must circulate bound to specific binding globulins, which increase their solubility.
• Men vs. women
  
  • In men, increased sex hormone–binding globulin (SHBG) lowers free testosterone –>Ž gynecomastia.
  • In women, decreased SHBG raises free testosterone –> hirsutism.
• OCPs, pregnancy increases SHBG (free estrogen levels remain unchanged).

Question 19

Thyroid hormones (T3/T4) (316)

• Definition
• Source
• Function

Answer 19

• Definition
  
  • Iodine-containing hormones that control the body’s metabolic rate.
• Source
  
  • Follicles of thyroid.
  • Most T3 formed in target tissues.
• Function (“4 B’s”)
  
  • Brain maturation
    
    • CNS maturation
  • Bone growth
    
    • Bone growth (synergism w/ GH)
  • β-adrenergic effects
    
    • Increased β1 receptors in heart = increased CO, HR, SV, contractility
  • Basal metabolic rate increased
    
    • ​Increased basal metabolic rate via increased Na+/K+-ATPase activity = increased O2 consumption, RR, body temperature
    • Increased glycogenolysis, gluconeogenesis, lipolysis

Question 20

Thyroid hormones (T3/T4) (316)

• Regulation
  
  • TRH
  • Wolff-Chaikoff effect
  • Thyroxine-binding globulin (TBG)
  • T4 vs. T3
  • Peroxidase
  • Propylthiouracil vs. methimazole
    
    • Propylthiouracil
    • Methimazole

Answer 20

• Regulation
  
  • TRH (hypothalamus) stimulates TSH (pituitary), which stimulates follicular cells.
    
    • Negative feedback by free T3, T4 to anterior pituitary decreases sensitivity to TRH.
    • Thyroid-stimulating immunoglobulins (TSIs), like TSH, stimulate follicular cells (e.g., Graves disease).
  • Wolff-Chaikoff effect
    
    • Excess iodine temporarily inhibits thyroid peroxidase –> decreased iodine organification Ž–> decreased T3/T4 production.
  • Thyroxine-binding globulin (TBG) binds most T3/T4 in blood
    
    • Only free hormone is active.
    • Decreased TBG in hepatic failure
    • Increased TBG in pregnancy or OCP use (estrogen increases TBG).
  • T4 vs. T3
    
    • T4 is major thyroid product; converted to T3 in peripheral tissue by 5’-deiodinase.
    • T3 binds receptors with greater affinity than T4.
  • Peroxidase is enzyme responsible for oxidation and organification of iodide as well as coupling of monoiodotyrosine (MIT) and diiodotyrosine (DIT).
  • Propylthiouracil vs. methimazole
    
    • Propylthiouracil inhibits both peroxidase and 5’-deiodinase.
    • Methimazole inhibits peroxidase only.