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ENDOC ENDOCRINE RINE EMBRY EMBRYOL OL OLOG OG OGYY 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.

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ENDOC ENDOCRINE RINE ANA ANATTOMY 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.

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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. 3 Pa Page ge

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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)

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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, a nd 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.

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UW: Nerve supply of the larynx: 

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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.

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ENDOC ENDOCRINE RINE PHYSI PHYSIO OLOG OGYY Insulin: SYNTHESIS: 

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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.

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SOURCE: 

Released from pancreatic β cells.

FUNCTION: 

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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.

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Transport of glucose    

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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

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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.

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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).

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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.

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SECRETION:  

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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.

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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. 

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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.

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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).

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Growth hormone (somatotropin):  

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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.

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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.”

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Antidiuretic hormone SOURCE: Synthesized in hypothalamus (supraoptic nuclei), stored and secreted by posterior pituitary.

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Regulates serum osmolarity (V2-receptors) and blood pressure (V1receptors). 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.

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Adrenal steroids and congenital adrenal hyperplasia:

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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...