Endocrine Physiology

Thyroid diverticulum arises from floor of primitive pharynx, descends into neck

Connected to tongue by thyroglossal duct; nl disappears, but may persist as pyramidal lobe of thyroid

Foramen cecum is normal remnant of thyroglossal duct

*Most common site of ectopic thyroid tissue: tongue

Thyroglossal duct cysts present as mass in anterior midline neck, moves when swallowing

Branchial cleft cyst in lateral neck from persistent cervical sinus

• Outer adult zone and inner active fetal zone
• -Adult zone is dormant during early fetal life
• -begins secreting cortisol late in gestation

• Cortisol secretion is controlled by ACTH and CRG from fetal pituitary AND placenta
• -Cortisol is responsible for fetal lung maturation and surfactant production

• 
• Cortex (from mesoderm)
• Medulla (from neural crest)

• -Zona Glomerulosa → Aldosterone (Salt/Na+)
• -Zona Fasciculata → Cortisol/glucocorticoids, sex hormones (Sugar)
• -Zona Reticularis → Sex hormones, e.g. androgens (Sex)

*GFR ... the deeper you go, the sweeter it gets

-Medulla → Catecholamines (Epi, NE)

• Renin-angiotensin → Zona glomerulosa (Aldosterone→salt)
• ACTH, hypothalamic CRH → Zona fasciculata (Glucocorticoids → sugar)
• ACTH, hypothalamic CRH → Zona Reticularis (androgens → sex)
• Preganglionic sympathetic fibers → Medulla (Catecholamines)

• Phyocromocytoma:
• -Most common tumor of the adrenal medulla in adults
• -Cause episodic hypertension

• Neuroblastoma:
• -Most common tumor of the adrenal medulla in children
• -Do NOT cause episodic hypertension

Left adrenal → left adrenal vein → left renal vein → IVC

Right adrenal → right adrenal vein → IVC

*Same as left and right gonadal

• Posterior pituitary (neurohypophysis)
• -Derived from neuroectoderm

• Anterior pituitary (adenophyophysis)
• -Derived from oral ectoderm (Rathke's pouch)

• Secretes vasopressin (ADH) and oxytocin
• -both made in hypothalamus
• -delivered to posterior pituitary via neurophysins (carrier proteins)

Derived from neuroectoderm

• Secretes: FLAT PiG
• -FSH
• -LH
• -ACTH
• -TSH
• -Prolactin
• -GH
• -Melanotropin (MSH)

• α subunit: hormone subunit common to TSH, LH, FSH, and hCG
• β subunit: determines hormone specificity

• Acidophils: GH, prolactin
• *B-FLAT: Basophils → FSH, LH, ACTH, TSH

• Islets of Langerhans are collections of α, β, and δ endocrine cells
• -Islets arise from pancreatic buds

• -α = glucagon (peripheral)
• -β = insulin (central)
• -δ = somatostatin (interspersed)

*Insuline (β cells) are inside

• Released from pancreas:
• -Glucose is major regulator of insulin release
• -ATP generated by glucose metabolism closes K⁺ channels and depolarizes β cell membrane → opens voltage gated Ca²⁺ channels
• -Calcium influx stimulates insulin secretion

*Insulin moves glucose Into cells

Insulin does not cross the placenta

• *BRICK L (insulin-independent glucose uptake):
• -Brain - GLUT-1 (insulin independent)
• -RBCs - GLUT-1 (insulin independent)
• -Intestine - GLUT-2 (bidirectional)
• -Cornea
• -Kidney - GLUT-2 (bidirectional)
• -Liver - GLUT-2 (bidirectional)

• -β islet cells have GLUT-2 (bidirectional)
• -GLUT-4 (insulin dependent): adipose tissue, skeletal muscle

• *Insulin does not cross the placenta
• 

• Anabolic effects of insulin:
• ↑ glucose transport in SKM and adipose
• ↑ glycogen synthesis and storage
• ↑ triglyceride synthesis and storage
• ↑ Na⁺ retention (kidneys)
• ↑ protein synthesis (muscles)
• ↑ Cellular uptake of K⁺ and amino acids
• ↓ glucagon release

• Hyperglycemia, GH, and β2-antagonists → ↑ insulin
• Hypoglycemia, somatostatin, and α2-agonists → ↓ insulin
• 

• GLUT-4 (insulin-dependent transporter)
• -Resting SKM
• -Adipose tissue

• GLUT-1 (insulin-independent transporter)
• -Brain
• -RBCs

-Brain depends on glucose metabolism under normal circumstances; ketone bodies in starvation

-RBCs always depend on glucose; no mitochondria for aerobic metabolism

Source: α cells in pancreas

• Function: Catabolic effects...
• -Glycogenolysis, gluconeogenesis
• -Lipolysis and ketone production

• Regulation:
• -Secreted in response to hypoglycemia
• -Inhibited by insulin, hyperglycemia, somatostatin

• -TRH → TSH, prolactin
• -Dopamine → (-) prolactin
• -CRH → ACTH, melanocyte-stimulating hormone, β-endorphin
• -GHRH → GH
• -Somatostatin → (-) GH, TSH
• -GnRH → FSH, LH
• -Prolactin → (-) GnRH

Source: anterior pituitary

• Function:
• -stimulates milk production
• -inhibits ovulation/spermatogenesis by inhibiting GnRH synthesis and release

• Regulation:
• -secretion is tonically inhibited by dopamine from hypothalamus
• -Prolactin in turn inhibits its own secretion (by increasing dopamine synthesis and secretion)
• -TRH ↑ prolactin secretion

*Dopamine antagonists (antipsychotics) and estrogens (OCPs, pregnancy) stimulate prolactin secretion

Dopamine agonists (bromocriptine) inhibit prolactin secretion

Source: Anterior pituitary

• Function:
• -Stimulates linear growth and muscle mass through Insulin like Growth Factor (IGF-1)/somatomedin secretion
• -Increases insulin resistance (diabetogenic)

• Regulation:
• -Pulsatile release in response to GHRH
• -Secretion ↑ during exercise and sleep
• -Secretions inhibited by glucose and somatostatin

• Acromegaly in adults
• Gigantism in children (...no, not Jordan)

• *All steroids require 3β
• -hydroxysteroid dehydrogenase

• Glomerulosa = mineralocorticoids (Aldosterone)
• -Enzymes required: 21-hydroxylase, 11β-hydroxylase

• Fasciculata = glucocorticoids (Cortisol)
• -Enzymes: 17α-hydroxylase, 21-hydroxylase, 11β-hydroxylase

• Reticularis = Androgens (Testosterone, DHT)
• -Testosterone → DHT (conversion requires 5α-reductase)

Periphery = Estrogen (Estradiol)

• 17α-hydroxylase deficiency:
• -↑ mineralocorticoids
• -↓ cortisol
• -↓ sex hormones

• Presentation:
• -hypertension, hypokalemia
• XY: ↓ DHT → pseudohermaphroditism (ambiguous genitalia, undescended testes)
• XX: external phenotype female; normal internal sex organs. lacks 2° sex characteristics

• 21-hydroxylase deficiency:
• -↓ mineralocorticoids
• -↓ cortisol
• -↑ sex hormones

• Presentation: *most common form
• -Hypotension, hyperkalemia, ↑ renin activity, volume depletion
• -Masculinization, leading to pseudohermaphroditism in female

• 11β-hydroxylase deficiency
• -↓ aldosterone; ↑11-deoxycorticosterone
• -↓ cortisol
• -↑ sex hormones

• Presentation:
• -Hypertension (11-deoxycorticosterone is a mineralocorticoid and is secreted in excess)
• -Masculinization

All are characterized by enlargement of both adrenal glands due to ↑ ACTH stimulation due to ↓ Cortisol

• Source: Zona fasciculata
• -Bound to corticosteroid-binding globulin (CBG)

• Function: Cortisol is BBIIG
• -Maintains Blood pressure: upregulates α1-receptors on arterioles to increase sensitivity to NE and EPI
• -↓ Bone formation
• -Anit-Inflammatory/Immunosuppressive:
•      -Inhibits production of leukotrienes and PGs
•      -Inhibits leukocyte adhesion → neutrophilia
•      -Blocks histamine release from mast cells
•      -Reduces eosinophils
•      -Blocks IL-2 production
• -↑ Insulin resistance (diabetogenic)
• -↑ Gluconeogenesis, lipolysis, proteolysis
• -Inhibits fibroblasts (causes striae)

• Regulation:
• -CRH (hypothalamus) stimulates ACTH release (pituitary) → cortisol production in adrenal ZF
• -Excess cortisol → ↓ CRH, ACTH, and cortisol secretion
• -Chronic stress induces prolonged secretion

Source: Chief cells - parathyroid gland

• Function: ↑ serum Ca²⁺, ↓ serum (PO₄^3-), ↑ urine (PO₄^3-)
• *"PTH = Phosphate Trashing Hormone"
• -↑ bone resorption of calcium and phosphate

• -↑ kidney reabsorption of calcium in distal convoluted tubule
• -↓ reabsorption of phosphate in proximal convoluted tubule

-↑ 1,25-(OH)₂ D₃ (calcitriol) production by stimulating kidney 1α-hydroxylase

*↑ production of M-CSF and RANK-L in osteoblasts, stimulating osteoclasts

• ↓ serum Ca²⁺ → ↑ PTH secretion
• ↓ serum Mg²⁺ → ↑ PTH secretion
• ↓↓ serum Mg²⁺ → ↓ PTH secretion
•       -↓ Mg²⁺ from diarrhea, aminoglycosides, diuretics, alcohol abuse

• Source: D₃ from sun exposure in skin
• -D₂ ingested (plants)
• -Both converted to 25-OH in liver, and 1,25-(OH)₂ (active form) in kidney

• Function: increases absorption of both Ca²⁺ and PO₄^3- in the gut
• -↑ absorption of dietary Ca²⁺ and PO₄^3-
• -↑ bone resorption of Ca²⁺ and PO₄^3-

• Regulation:
• -↑ PTH, ↓ [Ca²⁺], ↓ PO₄^3- causes ↑ 1,25-VitD production
• -1,25-VitD inhibits its own production (neg. feedback)

*PTH leads to ↑ Ca²⁺ and ↓ PO₄^3- reabsorption in the kidney

*24,25-VitD₃ is inactive form of Vitamin D

• Rickets in kids
• Osteomalacia in adults

Source: Parafollicular cells (C cells) of thyroid

• Function: Calcitonin opposes actions of PTH
• -not important in normal calcium homeostasis
• - ↓ bone resorption of calcium
• *"Calcitonin tones down calcium levels"

• Regulation:
• - ↑ serum Ca²⁺ causes calcitonin secretion

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

FLAT ChAMP

FSH, LH, ACTH, TSH, CRH, hCG, ADH (V2 receptor), MSH, PTH, calcitonin, GHRH, glucagon

• Think vasodilators:
• -ANP
• -NO (EDRF)

GGOAT

GnRH, GHRH, Oxytocin, ADH (V₁ receptor), TRH, histamine (H₁), angiotensin II, gastrin

VETTT CAP

Vitamin D, Estrogen, Testosterone, T₃/T₄, Cortisol, Aldosterone, Progesterone

• MAP kinase pathway
• Think growth factors

-Insulin, IGF-1, FGF, PDGF, EGF

• PIG; think acidophiles and cytokines
• -JAK/STAT pathway

Prolactin, Immunomodulators (e.g. cytokines IL-2, IL-6, IL-8, IFN) GH

• lipophilic; circulate bound to specific binding globulins (↑ their solubility)
• 

• In men: ↑ SHBG lowers free testosterone
• →gynecomastia

• In women: ↓ SHBG raises free testosterone
• →hirsutism
• →SHBG levels ↑ during pregnancy

Iodine-containing hormone that controls body's metabolic rate

• Source: Follicles of thyroid
• -Most T₃ is formed in target tissue

• Function:
• T₃ functions 4B's
• -Brain maturation
• -Bone growth (synergism with GH)
• -Beta-adrenergic effects (β1 receptor on heart...↑CO, HR< SV, contractility)
• -Basal metabolic rate ↑ (via ↑ Na⁺/K⁺-ATPase activity = ↑O₂ consumption, RR, body temp)
• -↑ glycogenolysis, gluconeogenesis, lipolysis

• Regulation: TRH (hypothalamus) stimulates TSH (pituitary), stimulates follicular cells
• -T3 → anterior pituitary (neg feedback) to ↓ sensitivity to TRH

TSIs (like TSH) stimulate follicular cells

Graves' disease has autoantibodies that activate follicular cells: hyperthyroidism

• Wolff-Chaikoff effect: excess iodine temporarily inhibits thyroid peroxidase 
• → ↓ iodine organification 
• → ↓ iodine organification 
• → ↓ T3/T4 production

• Peroxidase is enzyme responsible for oxidation and organification of iodide as well as coupling of MIT and DIT
• Propylthiouracil inhibits both peroxidase and 5'-deiodinase
• Methimazole inhibits peroxidase only
• 

• TBG binds most T3/T4
• only free hormone is active
• ↓TBG in hepatic failure
• ↑TBG inpregnancy or OCP use (estrogen ↑ TBG)

• T4 is the major thyroid product
• Converted to T3 in peripheral tissue by 5'-deiodinase
• T3 binds receptors with greater affinity than T4