Endocrine

*2º Hyperaldosteronism* - Cause: - Findings:

Cause: *Renal Diseases* - *Juxtaglomerular Cell Tumors* (Renin-Producing) - *Renal Hypoperfusion* → *Atherosclerosis* → *Fibromuscular Dysplasia* - Causes *Renovascular HTN* Findings: → *↑Renin/RAAS* → *↑Aldosterone*

*Nelson Syndrome* - Cause: - Findings: - Treatment:

Cause: - *ACTH-Secreting Pituitary Adenoma* (Cushing Disease) - Enlargement of it after *Bilateral Adrenalectomy* - ↓Cortisol = ↑↑ACTH Findings: - *Hyperpigmentation* (↑ACTH/↑MSH) - *Bitemporal Hemianopia* (Mass Effect) - *HA* Treatment: - Pituitary Irradiation - Surgical Resection

*Papillary Carcinoma* -Epidemiology: - Histology: - Association:

Epidemiology: - *Most Common* - Excellent Prognosis Histology: - *"Orphan Annie" Eyes*: (Empty Nuclei with Central Clearing) - *Psammoma Bodies* - *Nuclear Grooves* Associated with: - *RET Mutation* - *BRAF Mutation* - ***Childhood Irradiation***

*Follicular Carcinoma* -Epidemiology: - Histology: - Association:

Epidemiology: - Good Prognosis - *Hematogenous* Spread Histology: - *Invades Capsule & Vasculature* (Unlike Follicular Adenoma) Associated with: - *RAS Mutation*

*Undifferentiated/Anaplastic Carcinoma* -Epidemiology: - Findings:

Epidemiology: - Older Patients - Undifferentiated - *Worst Prognosis* Findings: - *Invades Local Structures* (Riedel Thyroiditis Mimics this by also Invading Local Structures)

*Pseudohypoparathyroidism Type 1A (Albright Hereditary Osteodystrophy)* - Findings: - Characteristics: - Genetics:

Findings/Labs: - *Unresponsive 'Kidney' to PTH* - *Hypocalcemia* Despite *↑PTH* - *↓Ca2+* - *↑PO4(3)-* - *↑PTH* Characteristics:: - *Shortened 4th/5th Digits* - *Short Stature* Genetics: - Autosomal Dominant - Defective *Gs Protein α-Subunit* - Causes *End-Organ Resistance to PTH* - Inherited from *Mother* - Due to *Imprinting*

*Pseudopseudohypoparathyroidism* - Findings/Labs: - Characteristics: - Genetics:

Findings/Labs: - No End-Organ Resistance to PTH - *Normal PTH* - *Normal Ca2+* Characteristics: - *Shortened 4th/5th Digits* - *Short Stature* Genetics: - Defective *Gs Protein α-Subunit* - Inherited from *Father*

Adrenal Cortex & Medulla Anatomy

From Outside to Inside: *Adrenal Cortex* → Zona *G*lomerulosa → Zona *F*asciculata → Zona *R*eticularis - *GFR* → Salt (Mineralocorticoids) → Sugar (Glucocorticoids) → Sex (Androgens) *"The Deeper you go, the Sweeter it Gets"* *Adrenal Medulla* → Chrommaffin Cells

*TRH* - Function:

Function: - *↑TSH* - *↑Prolactin* - ↑TRH (1°/2° Hypothyroidism) may increase *Prolactin Secretion* → Galactorrhea

*Somatostatin* - Function:

Function: - *↓GH* - *↓TSH* - Analogs used to treat *Acromegaly* - Side Effect: *Hypothyroidism*

*Prolactin* - Function:

Function: - *↓GnRH* - *Prolactinoma/Antipsychotics*: → Galactorrhea → Amenorrhea → Hypogonadism → Osteoporosis (↓Estrogen)

*Dopamine* - Function:

Function: - *↓Prolactin* - *↓TSH* - Dopamine Antagonists (*Antipsychotics*) can cause Galactorrhea due to Hyperprolactinemia

*CRH* - Function:

Function: - ↑ACTH - *↑MSH* - ↑β-Endorphin - ↓CRH in Exogenous Steroid Use

*GnRH* - Function:

Function: - ↑FSH - ↑LH - Suppressed by *Hyperprolactinemia* - Continuous GnRH Suppresses HPG Axis - Pulsatile GnRH → Puberty, Fertility

*GHRH* - Function:

Function: - ↑GH - Analog *Tesamorelin* used to treat HIV-Associated Lipodystrophy

*Neuroendocrine Tumors* in Various Organs:

Lungs: → *Small Cell Carcinoma* Adrenal Medulla: → *Neuroblastoma* → *Pheochromocytoma* Thyroid: → *Medullary Carcinoma* GI: → *Carcinoid Tumor* Pancreas: → *Islet Cell Tumor*

*Neuroendocrine Tumors*: - Origin: - Cells Contain: - Cells Secrete:

Neoplasms Originating from: - *Kulchitsky Cells* - *Enterochromaffin-Like Cells* Cells Contain: - Amine Precursor Uptake Decarboxylase (*APUD*) Cells Secrete: - *5-HIAA* - *Neuron-Specific Enolase* [NSE] - *Chromogranin A*

*Medullary Carcinoma* - Origin: - Histology: - Association:

Origin: - *Parafollicular C Cells* - *↑Calcitonin* Histology: - Cells in *Amyloid Stroma* (Calcitonin Breakdown) - Amyloid *Protein* Deposits - *Congo Red Stain* - *Apple-Green Birefringence* with Polarized Light Associated with: - *MEN 2A* - *MEN 2B* - *RET Mutations*

*Diabetes Insipidus (DI)* - Types: -Characteristics

Types: *Central DI*: - Lack of ADH *Nephrogenic DI*: - Fail to Respond to Circulating ADH Characteristics: - Thirst - Polyuria - Unable to Concentrate Urine Note: - ↑Urine Osmolality/Concentration During Water Deprivation Test indicates *Psychogenic Polydipsia*

Signaling Pathway of Endocrine Hormone: *cAMP*

"*FLAT CHAMP* *C*an *G*row *G*ood *H*umps": → *F*SH → *L*H → *A*CTH → *T*SH → *CRH* → *HCG* → *A*DH (V2-Receptor) → *M*SH → *P*TH → *C*alcitonin → *GHRH* → *G*lucagon/Epinephrine → *H*istamine (H2-Receptor)

Signaling Pathway of Endocrine Hormone: *IP3*

"*GOAT HAG*" → *GnRH* → *O*xytocin → *A*DH (V1-Receptor) → *TRH* → *H*istamine (H1-Receptor) → *A*ngiotensin II → *G*astrin

*Ghrelin* - Function: - Produced by: - ↑Production: - Association:

"Ghrelin makes you Hunger" Function: - Stimulates *Hunger* & *GH Release* - *Lateral Hypothalamic Nuclei* Produced by: - *Stomach* ↑Ghrelin Production Associated with: - *Sleep Deprivation* - *Prader-Willi Syndrome*

*Leptin* - Function: - Produced by: - Mutation: - ↓Production:

"Leptin keeps you Thin" Function: - *Satiety* Hormone/Fullness - *Ventromedial Hypothalamic Nuclei* Produced by: - *Adipose Tissue* Mutation of Leptin Gene: - *Congenital Obesity* ↓Leptin Production Associated with: - *Sleep Deprivation* - *Starvation*

Signaling Pathway of Endocrine Hormone: *cGMP*

- Think *Vasodilators* & *cGMP* "*BAN*": → *BNP* (Brain Natriuretic Peptide) → *ANP* (Atrial Natriuretic Peptide) → *NO*

*Multiple Endocrine Neoplasias (MEN)* - Defects: - Associations:

*"All MEN are Autosomal Dominant"* *MEN 1*: → *Pituitary Tumors* (Prolactin, GH) → *Parathyroid Adenomas* (Hyperparathyroid; Kidney Stones) → *Pancreatic Endocrine Tumors* - Glucagonomas - Insulinomas - VIPomas - Zollinger-Ellison Syndrome (Ulcers) Associated with: - Mutation of *MEN1* (*Menin*) (Tumor Suppressor, Chromosome 11) *MEN 2A* → *Parathyroid Hyperplasia* → *Medullary Thyroid Carcinoma* → *Pheochromocytoma* Associated with: - *Marfanoid Habitus* - Mutation in *RET* (Receptor Tyrosine Kinase) *MEN 2B* → *Medullary Thyroid Carcinoma* → *Pheochromocytoma* → *Mucosal Neuromas* - Oral/Intestinal Ganglioneuromatosis Associated with: - *Marfanoid Habitus* - Mutation in *RET* *MEN 1 = 3 P's*: Pituitary, Parathyroid, Pancreas *MEN 2A = 2 P's*: Parathyroids, Pheochromocytoma *MEN 2B = 1 P*: Pheochromocytoma

*3º Adrenal Insufficiency* - Defect: - Symptoms:

*"Tertiary from Treatment"* Defect: - *Chronic Exogenous Steroid Use* - Precipitated by *Abrupt Withdrawal* - ↓CRH, ↓ACTH, ↓Cortisol Symptoms: - *Aldosterone* Synthesis Preserved due to *Intact RAAS* - No Hypotension - No Hyperkalemia - No Metabolic Acidosis - *No Skin/Mucosal Hyperpigmentation* (↓ACTH, ↓MSH)

*Waterhouse-Friderichsen Syndrome*

*Acute 1° Adrenal Insufficiency* → *Adrenal Hemorrhage* → Due to *Neisseria Meningitidis* → *DIC* → *Endotoxic Shock*

*Insulin-Independent Transporters*:

*BRICKS PL*ease: *β*-Islet Cells, *B*rain, *R*BCs, *I*ntestine, *C*ornea, *K*idney, *S*permatocytes, *P*lacenta, *L*iver *GLUT1*: → Brain → RBCs → Cornea → Placenta *GLUT2* (*Bidirectional, Slow at ↓Glucose*): → *β Islet Cells* → *Liver* → Kidney → Intestine *GLUT3*: → Brain → Placenta *GLUT5* (Fructose): → Spermatocytes → GI Tract

- Normal Remnant of Thyroglossal Duct is called:

*Foramen Cecum*

*Insulin-Dependent Glucose Transporters*:

*GLUT4*: → Skeletal Muscle → Adipose Tissue (*Exercise* can ↑GLUT4 Expression)

Endocrine Pancreas Cell Types

*Islets of Langerhans* within *Pancreas* - Islets arise from Pancreatic Buds - Contain *α, β, δ* Endocrine Cells *α* = *Glucagon* (Peripheral) *β* = *Insulin* (Central) *δ* = *Somatostatin* (Interspersed) *Insulin* (β cells) *"Inside"*

Thyroid Hormone Inhibitors:

*Propylthiouracil* (*PTU*): - Inhibits Thyroid Peroxidase - Inhibits 5′-Deiodinase (*T4 → T3*) *Methimazole*: - Inhibits Thyroid Peroxidase Only *Glucocorticoids*: - Inhibit Conversion of *T4 → T3* *ß-Blockers* - Used for Hyperthyroidism - For Control of Adrenergic Symptoms (Tachycardia, Tremor, Anxiety) - Inhibit Conversion *T4 → T3* All Drugs *Inhibiting Conversion T4 → T3*: - *PTU* (*Propylthiouracil*) - *Glucocorticoids* - *ß-Blockers* - Amiodarone *Perchlorate* & *Pertechnetate* - Inhibit Na/Iodine Symporter

*Congenital Hypothyroidism (Cretinism)* - Cause: - Findings:

*Severe Fetal Hypothyroidism* Caused by: → Maternal Hypothyroidism → Thyroid Agenesis → Thyroid Dysgenesis → Iodine Deficiency → Dyshormonogenetic Goiter Findings: - *Puffy-Faced* - *Protruding Umbilicus* - *Protuberant Tongue* - *Large Anterior Fontanelle* - *Poor Brain Development*

*Thyroglossal Cyst* vs *Branchial Cleft Cyst*

*Thyroglossal Cyst* - Persistent Thyroglossal Duct - *Anterior* Midline Neck Mass - *Moves* with Swallowing *Branchial Cleft Cyst* - Persistent Cervical Sinus - *Lateral* Neck, Anterior to SCM - *Immobile* with Swallowing

*Adrenal Cortex & Medulla* - Regulated By: - Hormone Class: - Hormone Produced:

*Zona Glomerulosa*: - 1º Regulation By: *Angiotensin II* - Hormone Class: *Mineralocorticoids* - 1º Hormone Produced: *Aldosterone* *Zona Fasciculata*: - 1º Regulation By: *CRH, ACTH* - Hormone Class: *Glucocorticoids* - 1º Hormone Produced: *Cortisol* *Zona Reticularis*: - 1º Regulation By: *CRH, ACTH* - Hormone Class: *Androgens* - 1º Hormone Produced: *DHEA*, *Androstenedione* *Chrommaffin Cells* - 1º Regulation By: *'Pre'ganglionic Sympathetic Fibers* - Hormone Class: *Catecholamines* - 1º Hormone Produced: *Epi, NE*

*Cushing Syndrome* - Causes: - Symptoms:

*↑Cortisol* Causes: → *Exogenous Corticosteroids* (Autoimmune/Inflammatory Diseases) - ↑Cortisol - ↓ACTH - *Bilateral Adrenal Atrophy* → *Primary Adrenal Adenoma, Hyperplasia, Carcinoma* (15%) - ↑Cortisol - ↓ACTH - *Atrophy of Uninvolved Adrenal Gland* → *ACTH-Secreting Pituitary Adenoma* (Cushing Disease; 70%) → *Ectopic ACTH Secretion* (<15%) (Small Cell Lung Cancer) (Renal/Clear Cell Carcinoma) - ↑ACTH - ↑Cortisol - *Bilateral Adrenal Hyperplasia* Symptoms: Cortisol = "A BIG FIB" - *Moon Facies* - *Buffalo Hump* - *Truncal Obesity* - *Abdominal Striae* - *Peripheral Wasting* (Skinny Arms/Legs) - Skin Changes (Thinning, Striae) - Hypertension - Hyperglycemia (Insulin Resistance) - Weight Gain - Amenorrhea - Osteoporosis - Immunosuppression

*Pituitary Adenoma* - Nonfunctional Tumor Findings: - Prolactinoma in Women/Men: - Treatment:

- *Benign* Tumor - Nonfunctional (Silent) Tumors present with *Mass Effect*: → *Bitemporal Hemianopia* → *Hypopituitarism* → *HA* - Functional (Hormone Producing) Tumor Presentation is Based on the Hormone Produced *Prolactinoma* in Women: → *Galactorrhea* → *Amenorrhea* (↓GnRH) → *↓Bone Density* due to Estrogen Suppression (↓GnRH) *Prolactinoma* in Men: → *Low Libido* (↓GnRH) → *Infertility* (↓GnRH) Treatment: - Dopamine Agonists → *Bromocriptine* → *Cabergoline*

*Wolff-Chaikoff Effect*:

- *Excess Iodine* - *Inhibits Thyroid Peroxidase* - ↓Oxidization, Organification, Coupling → *Hypothyroid*

*Insulin* - Regulation

- *Glucose* is the Major Regulator of Insulin Release *Insulin Response Upregulated* with: - *Oral* (vs IV) *Glucose*, because *Incretins* like *Glucagon-like Peptide 1* (*GLP-1*) & Glucose-Dependent Insulinotropic Polypeptide (*GIP*) are Released After Meals & *↑β-Cell Sensitivity to Glucose* Insulin Release: - ↓ by *α2* - ↑by *β2* - *Glucose* enters β Cells via *GLUT2* ③ - Glucose is metabolized by *Glucokinase* to G-6-P, then ATP - *↑ATP* Generated from Glucose Metabolism/Glycolysis ④ - *Closes ATP-Sensitive K+ Channels* ⑤ (Target of *Sulfonylureas*) - *Depolarizes* β Cell Membrane ⑥ - *Voltage-Gated Ca2+ Channels* Open & Ca2+ Influx ⑦ - Stimulation of *Insulin Exocytosis* ⑧

*Thyroid Hormones (T3/T4)*: - Source: - Function: - Regulation

- *Iodine*-Containing Hormones that Control Body's Metabolic Rate Source: - *Follicles* of Thyroid Function: *4 B's*: → *Bone Growth* (Synergism with GH) → *Brain Maturation* → *↑β1-Adrenergic Receptors in Heart* - ↑CO, ↑HR, ↑SV, ↑Contractility → *↑Basal Metabolic Rate* via *↑Na/K-ATPase* - ↑O2 Consumption - ↑Body Temperature - ↑RR → ↑*Glycogenolysis, Gluconeogenesis, Lipolysis* - *T4* is the Major Thyroid Product - *T4 → T3* by *5′-Deiodinase* - Most *T3* Formed at *Target Tissues* - *T3* Binds Nuclear Receptor with *Greater Affinity* than T4 - Function of *Thyroid Peroxidase*: → *Oxidation* [I → I(2)] → *Organification* [I(2) → DIT/MIT] → *Coupling* of MIT/DIT to T4/T3 - *DIT + DIT = T4* - *DIT + MIT = T3* Regulation: - TRH → TSH → Follicular Cells - Follicular Cells may also be Stimulated by *Thyroid Stimulating Immunoglobulin* (*TSI*) in Graves Disease

Signaling Pathway of Endocrine Hormone: *Nonreceptor Tyrosine Kinase*

- *JAK/STAT Pathway* - Think *Acidophils* & *Cytokines* → *P*rolactin → *G*H → *Cytokines: IL-2, IL-6, IFN* → *G-CSF* → *Erythropoietin* → *Thrombopoietin*

Signaling Pathway of Endocrine Hormone: *Receptor Tyrosine Kinase*

- *MAP Kinase Pathway* - Think *Growth Factors (GF)* → *Insulin* → *IGF-1* (From Growth Hormone) → F*GF* → PD*GF* → E*GF*

Thyroid Development

- *Thyroid Diverticulum* arises from Floor of *Primitive Pharynx* & Descends into Neck where it grows into Thyroid Gland - Thyroid is connected to Tongue by *Thyroglossal Duct*, which normally *Disappears* - Thyroglossal Duct may *Persist* as: → *Pyramidal Lobe of Thyroid* → *Thyroglossal Cyst* → *Ectopic Lingual Thyroid* (Tongue) - Removal of *Pyramidal Lobe* may result in *Hypothyroidism* if it is the only Thyroid Tissue present

- *Thyroxine-Binding Globulin* (*TBG*): - ↓TBG Cause: - ↑TBG Cause:

- *Thyroxine-Binding Globulin* (*TBG*) binds most T3/T4 in Blood - *Only FREE T3/T4 is Active* *Total* T3/T4 = - *T3/T4 Bound to TBG* - *Free T3/T4* - *↑Total T3/T4* may be due to *↑TBG* (Pregnancy) or *↑Free T3/T4* - Only *Free T3/T4* Negatively Feedback on *TSH* Cause of ↓TBG: → *Liver Failure* → *Nephrotic Syndrome* → *Glucocorticoid Use* Cause of ↑TBG: → *Pregnancy* → *OCP Use* (Estrogen ↑TBG)

*Endocannabinoids* - Function:

- Act at *Cannabinoid Receptors* - In Hypothalamus & Nucleus Accumbent - *↑Appetite* - Exogenous Cannabinoids cause "The Munchies"

Congenital Adrenal Hyperplasias

- All Congenital Adrenal Enzyme Deficiencies are Characterized by: → *Enlargement* of Both *Adrenal Glands* → *Skin Hyperpigmentation* (↑ACTH (↑MSH) due to ↓Cortisol) Note: - *Corticosterones* act like *Aldosterone* → 11-Deoxycorticosterone → Corticosterone → 11-Deoxycortisol

*Insulin* - Function

- Insulin Binds Insulin Receptors (*Tyrosine Kinase Activity* ①) - Induces Glucose Uptake (**Carrier-Mediated Transport*) into *Insulin-Dependent Tissue* via *GLUT4* ② - Insulin-Dependent Tissue include *Skeletal Muscle* & *Adipose Tissue* *Anabolic Effects* of Insulin: - ↑Glucose Transport in Skeletal Muscle & Adipose Tissue - ↑*Glycogen* Synthesis & Storage - ↑*Triglyceride/Fatty Acid* Synthesis - ↑*Protein* Synthesis (Muscles) - ↑*Cell Uptake of K+ & Amino Acids* - ↑*Na+ Retention* (Kidneys) - ↓*Glucagon* Release - ↓*Lipolysis* in Adipose Tissue - ↓*Proteolysis* - Unlike *Glucose* (Crosses Placenta), *Insulin 'Does Not' Cross Placenta* - *Brain* Utilizes *Glucose* for Metabolism Normally & *Ketones* during Starvation - *RBCs* Utilize *Glucose Only* because they *Lack Mitochondria* & cannot use Aerobic Metabolism

*Jod-Basedow Phenomenon*

- Patient with *Iodine Deficiency* - *↑Iodine*/Iodine Supplied → *Hyperthyroidism* - Opposite of *Wolff-Chaikoff Effect* - ↑Iodine - Inhibits Thyroid Peroxidase → Hypothyroid

Signaling Pathway of *Steroid Hormones* - SHBG

- Steroid Hormones are *Lipophilic* & therefore must *Circulate Bound to Specific Binding Globulins*, which ↑ their Solubility - *Sex Hormone-Binding Globulin* (*SHBG*) binds *Testosterone* In Men: *↑SHBG* = *↓Free Testosterone* → *Gynecomastia* In Women: *↓SHBG* = *↑Free Testosterone* → *Hirsutism* ↑SHBG due to: - *Pregnancy* - *OCPs*

*Cushing Syndrome* - Diagnosis with Screening Tests

- ↑Free Cortisol on 24-hr Urinalysis - ↑Midnight Salivary Cortisol - No Suppression with Overnight Low-Dose Dexamethasone Test - Measure Serum *ACTH*: → If *↓ACTH*: - *Adrenal Tumor* - *Exogenous Glucocorticoids* [↑Cortisol → ↓ACTH] → If *↑ACTH*: - *Cushing Disease* - *Ectopic ACTH Secretion* (Small Cell Lung Cancer) (Renal/Clear Cell Carcinoma) [↑ACTH → ↑Cortisol] *High-Dose Dexamethasone Suppression Test*: - Ectopic ACTH Secretion *Will Not Decrease* with Dexamethasone because the Source is Resistant to Negative Feedback - ACTH Secretion from Cushing Disease *Will Decrease* with Dexamethasone because of Negative Feedback on ACTH in Pituitary *CRH Stimulation Test*: - Ectopic ACTH Secretion *Will Not Increase* with CRH because Pituitary ACTH is Suppressed - ACTH Secretion from Cushing Disease *Will Increase* with CRH Stimulation

*Diabetes Mellitus* - Acute Manifestations: - Rare Causes: - Diagnosis

Acute Manifestations: - Polydipsia - Polyuria - Polyphagia - Weight Loss - DKA (Type 1) - Hyperosmolar Coma (Type 2) Rare Causes: - Unopposed Secretion of GH & Epi - Patients on Glucocorticoid Therapy (Steroid Diabetes) Diagnosis: *HbA1c* - Diagnostic Cutoff: *≥6.5%* - Average Blood Glucose Last 3 Months *Fasting Plasma Glucose*: - Diagnostic Cutoff: *≥126* mg/dL - Fasting for > 8 Hours *2-Hour Oral Glucose Tolerance Test*: - Diagnostic Cutoff: *≥200* mg/dL - 2 Hours After Consumption of 75g of Glucose in Water *Random Glucose ≥200 + Symptoms*

*Osteitis Fibrosa Cystica*

Associated with: - *1° Hyperparathyroidism* - ↑PTH Findings: - *Cystic Bone Spaces filled with Brown Fibrous Tissue* - *"Brown Tumor"* - Osteoclasts - Deposited Hemosiderin from Hemorrhages - Causes Bone Pain

*Lymphoma* - Association:

Associated with: - *Hashimoto Thyroiditis* (Non-Hodgkin B-Cell Lymphoma)

*Laron Syndrome (Dwarfism)* - Cause: - Lab Findings: - Characteristics:

Cause: - *Defective GH Receptors* - *↓Linear Growth* Lab Findings: - *↑GH* - *↓IGF-1* Characteristics: - Short Height - Small Head Circumference - Saddle Nose - Prominent Forehead - Delayed Skeletal Maturation - Small Genitalia

*Nephrogenic Diabetes Insipidus*: - Cause: - Findings: - Water Deprivation Test: - *Treatment*:

Cause: - ADH Receptor Mutation - Hypercalcemia - Hypokalemia - *Demeclocycline* (ADH Antagonist) - *Lithium* Findings: - *Normal/↑ADH* - *Dilute Urine* - *Concentrated Serum* - Urine Specific Gravity <1.006 - Serum Osmolality >290 mOsm/kg - Hyperosmotic Volume Contraction Water Deprivation Test: - Minimal Change in Urine Osmolality After Administration of ADH Analog Treatment: - *Hydrochlorothiazide/HCTZ Diuretic* - *Amiloride* (*K+ Sparring Diuretic*) - *Indomethacin* - Hydration - Dietary Salt Restriction

*Hypoparathyroidism* - Cause: - Findings:

Cause: - Accidental Surgical Excision - Autoimmune (Hashimoto's) - DiGeorge Syndrome Findings: - *Hypocalcemia* - *Hyperphosphatemia* - *Tetany* - *Chvostek Sign* (Tapping of Facial Nerve/Cheek Contracts Facial Muscles) - *Trousseau Sign* (Occlusion of Brachial Artery with BP Cuff Causes Carpal Spasm)

*Familial Hypocalciuric Hypercalcemia* - Cause: - Findings:

Cause: - Autosomal Dominant - *Defective Ca2+ Sensing Receptors (CaSR)* Findings: - *Higher than Normal Ca2+ Levels* Required to *Suppress PTH* - *Excessive Renal Ca2+ Reuptake* → *Hypercalcemia* → ***Hypocalciuria*** → *Normal/↑PTH*

*1º Hyperaldosteronism* - Cause: - Findings:

Cause: - Bilateral Adrenal *Hyperplasia* - Adrenal *Adenoma* (*Conn Syndrome*) Findings: - ↑Aldosterone - ↓Renin

*1º Hyperparathyroidism* - Cause: - Findings:

Cause: - Parathyroid *Adenoma* - Parathyroid *Hyperplasia* Findings: - *↑PTH* - Hypercalcemia - Hypophosphatemia - ↑cAMP in Urine - Hypercalciuria (*Renal Stones*) - Polyuria (*Thrones*) - Osteitis Fibrosa Cystica (*Bones*) - Abdominal Pain/Constipation (*Groans*) - Depression (*Psychiatric Overtones*) - *↑ALP* (↑PTH) *"Stones, Thrones, Bones, Groans, Psychiatric Overtones"*

*Central Diabetes Insipidus*: - Cause: - Findings: - Water Deprivation Test: - *Treatment*:

Cause: - Pituitary Tumor - Autoimmune Disease - Ischemic Encephalopathy - Idiopathic - *Head Trauma* - *Surgery* Findings: - *↓ADH* - *Dilute Urine* - *Concentrated Serum* - Urine Specific Gravity <1.006 - Serum Osmolality >290 mOsm/kg - Hyperosmotic Volume Contraction Water Deprivation Test: - >50% ↑Urine Osmolality After Administration of ADH Analog Treatment: - *Desmopressin Acetate* (ADH Analog) - Hydration

*3º Hyperparathyroidism* - Cause: - Findings:

Cause: - Refractory Hyperparathyroidism due to **Chronic Renal Disease** Findings: - *↑↑PTH* - *↑Ca2+* (*Hypercalcemia*)

*Hyperosmolar Hyperglycemic Nonketotic Syndrome (HHNS)* - Defect: - Findings: - Symptoms: - Labs: - Treatment:

Complication of *Type 2 DM* Defect: - *Hyperglycemia-Induced Dehydration* - *↑Serum Osmolality/Concentration* - In Elderly with Limited Ability to Drink Findings: - *Hyperglycemia* - *Excessive Diuresis* - *Dehydration* - Eventual Onset of *HHNS* (Ketone Production Inhibited by Presence of *Insulin* in Type 2 DM) Symptoms: - Thirst - Polyuria - Lethargy - Neurological Deficits (Seizures) - Can Progress to *Coma & Death* Labs: - Hyperglycemia (>600 mg/dL) - ↑Serum Osmolality (>320mOsm/kg) - *No Acidosis*/No DKA Treatment: - *Aggressive IV Fluids* - *Insulin Therapy*

*Graves Disease* - Defect: - Pathology: - Symptoms: - Association: - Histology:

Defect: - Most Common *Hyperthyroidism* Pathology: - *Autoimmune* - *TSI*: *Thyroid-Stimulating Ig* Stimulates TSH Receptors on Thyroid (IgG; Type *II* Hypersensitivity): Symptoms: → *Hyperthyroid* → *Pretibial Myxedema* → *Exophthalmos*: - Retroorbital Space T-Cells Infiltration - ↑Cytokines (TNF-α, IFN-γ) - ↑Fibroblast Secretion of GAGs - ↑Osmotic Muscle Swelling Treat with: *Glucocorticoids* For Anti-Inflammatory Effects Associated with: - *HLA-DR3 & HLA-B8* Histology: - *Scalloped Colloid*

*Diabetic Ketoacidosis (DKA)* - Defect: - Symptoms: - Labs: - Complication: - Treatment:

Complication of *Type I DM* Defect: - Due to *↑Insulin Requirements* from *↑Stress* (↑Anti-Insulin: Cortisol) - *No Insulin Production* in Type I DM - *↑Lipolysis* & ↑Free Fatty Acids, which are then made into Ketone Bodies: *Ketogenesis* (β-Hydroxybutyrate > Acetoacetate) - *Endogenous Insulin* in Type 2 DM *Prevents Lipolysis* Symptoms: "*DKA* is *D*eadly": - *D*elirium - *Kussmaul Respirations* (Rapid/Deep) - *A*bdominal Pain/N/V - *Dehydration* - *Fruity Breath Odor* (Acetone) Labs: - ↑Blood Ketone Levels - Hyperglycemia - ↑H+, ↓pH - ↓HCO3 (Metabolic Acidosis) - *Anion Gap Metabolic Acidosis* - *Hyperkalemia* (But Depleted Intracellular K+ due to Cellular Shifts from *↓Insulin & Acidosis*) Complications: - Life-Threatening *Mucormycosis* (Caused by *Rhizopus* Infection) - Cerebral Edema - Cardiac Arrhythmias Treatment: - ***IV Fluids*** - *IV Insulin* - *K+* (Replete Intracellular Stores) - Glucose (Hypoglycemia Prevention)

*Acromegaly* - Defect: - Findings: - *↑Risk of*: - *Diagnosis*: - Treatment:

Defect/Cause: - *Excess GH in Adults* - Caused by *Pituitary Adenoma* Findings: - *Large Jaw* - Large Tongue with Deep Furrows - Deep Voice - Large Hands/Feet - Coarsening Facial Features - Aging - Frontal Bossing - Diaphoresis (Sweating) - Impaired Glucose Tolerance (*Insulin Resistance*) - *Organ Hypertrophy* ↑Risk of: - *Colorectal Polyps/Cancer* Diagnosis: - GH Unstable due to Pulsatile GHRH - *↑IGF-1* - *Failure to ↓GH following Oral Glucose* - *Pituitary Mass* on Brain MRI Treatment: - Pituitary Adenoma Resection - *Octreotide* (Somatostatin Analog) - *Pegvisomant* (GH Receptor Antagonist)

*Gigantism* - Defect: - Findings: - Cause of Death:

Defect: *↑GH in Children* Findings: - *↑Linear Bone Growth* - If Occurs before *Epiphyseal Closure* Cause of Death: - *HF*

*2º Hyperparathyroidism* - Defect: - Cause: - Findings:

Defect: - *2° Parathyroid Hyperplasia* - Due to ***Renal Disease*** - Causes *Hypovitaminosis D* Cause: - *↓Ca2+* - *↑PO4(3)−* - *↑PTH* Findings: - Hypocalcemia - Hyperphosphatemia - ↑PTH - *↑ALP* *Renal Osteodystrophy* - Renal Disease - 2°/3° Hyperparathyroidism - Bone Lesions

*Pheochromocytoma* - Defect: - Origin: - Association: - Symptoms: - Urine: - Treatment: - Rule of 10s:

Defect: - *Adrenal Medulla* Tumor in *Adults* - *Neuroendocrine Tumor* Derivation/Origin: - *Chromaffin Cells* of *Neural Crest Cells* Associated with: → *NF-1* → *VHL* → *RET* (*MEN2A, MEN2B*) Symptoms: - Secrete *Epi, NE, Dopamine* - Symptoms occur in *"Spells"* - *Episodic HTN* - *HA* Episodic Hyperadrenergic Symptoms (5 P's): → Pressure (↑BP) → Pain (HA) → Palpitations (Tachycardia) → Perspiration → Pallor Urine: - *Metanephrines: HVA/VMA* in Urine Treatment: - First α-Antagonists: *Phenoxybenzamine* - Then β-Blockers: *Propranolol* - α-Blockade before β-Blockers to Avoid *Hypertensive Crisis* "Phenoxybenzamine (16) is given for Pheochromocytoma (16)" Rule of 10's: - 10% Malignant - 10% Bilateral - 10% Extra-Adrenal - 10% Calcified - 10% Kids

*Neuroblastoma* - Defect: - Origin - Location of Occurrence: - Presentation: - Pathology: - Association: - Classified as:

Defect: - *Adrenal Medulla* Tumor in *Children* - A *Neuroendocrine Tumor* Origin: - *Neural Crest Cells* Location of Occurrence: - Anywhere along *Sympathetic Chain* Presentation: - Abdominal *Mass* - *Irregular* - Mass Can *Cross Midline* - *Opsoclonus-Myoclonus Syndrome* ("Dancing Eyes-Dancing Feet") Compared with *Wilms Tumor*: - Abdominal *Mass* - *Smooth* - *'W'ilms 'W'on't Cross Midline* Pathology: - * Metanephrines: HVA/VMA* in Urine (Catecholamine Metabolites) - *Homer-Wright Rosettes* - *Bombesin ⊕* - *Neuron-Specific Enolase (NSE) ⊕* Associated with: - Overexpression of *N-myc Oncogene* Classified as: - Amine Precursor Uptake Decarboxylase (*APUD*) Tumor

*Type 1 DM* - Defect: - HLA Association: - Histology:

Defect: - *Autoimmune* Destruction of β-Cells - *Glutamic Acid Decarboxylase* (GAD 65) Antibodies - *No Insulin Production* Histology: - *HLA DR3* - *HLA DR4* Histology: - *Islet Leukocytic Infiltrate* Symptoms: - *Polyuria, Polydipsia* - *Weight Loss* Note: - In Type 1 DM, *No functioning Insulin or Glucagon* - In Hypoglycemia: → Insulin Will Not Decrease → Glucagon Will Not Increase → Patients Dependent on *Epinephrine* (Epinephrine-Stimulated Hepatic Glycogenolysis)

*Thyroid Adenoma* - Defect: - Histology:

Defect: - *Benign* Growth of Thyroid Histology: - *Follicular* - *No Capsular or Vascular Invasion* (Unlike Follicular Carcinoma)

*Zollinger-Ellison Syndrome* - Defect: - Symptoms: - Secretin Stimulation Test: - Association:

Defect: - *Gastrin-Secreting Tumor* (*Gastrinoma*) - Tumor of *Pancreas or Duodenum* - *↑Gastrin* - Induces Parietal Cells to *↑HCl* - *Ulcers* in *Duodenum/'Jejunum'* Histology: - Gastrin Hypersecretion - *Parietal Cell Hyperplasia* - Enlarged Gastric *Rugal Folds* Secretin Stimulation Test: → *Positive* - *Secretin* Normally Inhibits Gastrin - In Zollinger-Ellison, *Gastrin Levels Remain Elevated* After Administration of *Secretin* Association: - *MEN 1* (Pancreatic Tumor)

*Hyperaldosteronism* - Defect: - Symptoms:

Defect: - *↑Aldosterone* from Adrenal Gland Symptoms: - *Hypertension* - *Hypokalemia* (↓K+) - *Metabolic Alkalosis* (↓H+) → **Muscle Weakness** (↓K+) → **Paresthesia**

*Type 2 DM*: - Defect: - Histology:

Defect: - *↑Blood Glucose* - *↑Resistance to Insulin* - Progressive Pancreatic *β-Cell Failure* Histology: - Islet *Amyloid* Polypeptide Deposits

*Carcinoid Syndrome* - Defect - Features: - Symptoms: - Labs: - Treatment: - Rule of 1/3:

Defect: - Caused by *Carcinoid Tumors* - Secrete *Serotonin (5-HT)* Features: - *Neuroendocrine Cell*→*Rosettes* - Metastatic *Small Intestine/GI Tumors* - Secrete *↑↑Serotonin (5-HT)* - *Not Seen* if Tumor is Limited to *GI Tract* - *5-HT Metabolized by Liver First-Pass* - *Seen* if Tumor Metastasizes to *Liver* - Most Common Malignancy in *Small Intestine* Symptoms: - *Diarrhea* - *Flushing* - *Wheezing* - *Right-Sided Valvular Heart Disease* (Tricuspid Regurg, Pulmonic Stenosis) - *Tryptophan* used up by *↑Serotonin* - ↓Serotonin left for *Vit B3* - *Niacin Deficiency*: Pellagra (Dermatitis, Diarrhea, Dementia) Labs: - *↑5-HIAA* in Urine (5-Hydroxyindoleacetic Acid) Treatment: - Surgical Resection - Somatostatin Analog (*Octreotide*) Rule of 1/3: - 1/3 are Multiple - 1/3 Metastasize - 1/3 Present with 2nd Malignancy

*Thyroid Storm* - Defect: - Presentation: - Treatment:

Defect: - Complication of *Hyperthyroidism* that is *Poorly Treated/Untreated* - Worsens with *Acute Stress*: Infection, Trauma, Surgery Presentation: - *Fever* - Agitation - Diarrhea - Delirium - Coma - ↑LFTs - *Tachyarrhythmia* (*Cause of Death*) Treatment: *"4 P's"* → *β-Blockers* (*Propranolol*) → *Propylthiouracil* (*PTU*) → *Corticosteroids* (*Prednisolone*) → *Potassium Iodide* (*KI*)

*1º Adrenal Insufficiency* - Defect: - Symptoms: - Treatment: - Acute/Chronic:

Defect: - Deficiency of *Aldosterone & Cortisol* Production due to Loss of Adrenal Gland Function Symptoms: - *Hypotension* (Hyponatremic) - *Hyperkalemia* - *Metabolic Acidosis* - *Skin/Mucosal Hyperpigmentation* (Due to *↑MSH*, a Byproduct of ACTH Production from POMC) *Acute* 1º Adrenal Insufficiency: → *Waterhouse-Friderichsen Syndrome* - Sudden Onset (Ex: Hemorrhage, DIC) - Possible Shock in Adrenal Crisis - *Bilateral Hemorrhagic Infarction of Adrenal Glands* *Chronic* 1º Adrenal Insufficiency: → *Addison Disease* - Due to Adrenal Atrophy or Destruction - Autoimmune Destruction most common in the Western world - TB Destruction most common in the Developing World

*Subacute Granulomatous Thyroiditis* (*De Quervain*) - Defect: - Histology: - Findings:

Defect: - Following a *Flu-Like Illness* - *Self-Resolve* - Early Hyperthyroid - Followed by *Hypothyroid* Histology: - *Granulomatous Inflammation* - *Lymphocytic* Infiltration - *Multinucleated Giant Cells* Findings: - *↑ESR* - Jaw Pain - *Tender Thyroid* "De Quer*vain* is associated with *Pain*"

*Adrenal Insufficiency* - Defect: - Symptoms: - Treatment: - Diagnosis:

Defect: - Inability of Adrenal Glands to generate enough *Glucocorticoids +/− Mineralocorticoids* Symptoms: - Weakness - Fatigue - Muscle Aches - Weight Loss - GI Disturbances - Orthostatic Hypotension - Salt/Sugar Cravings Treatment: - Glucocorticoid/Mineralocorticoid Replacement Diagnosis: - 1° Adrenal Insufficiency = ↓Cortisol, ↑ACTH - 2°/3° Adrenal Insufficiency = ↓ACTH, ↓Cortisol (Hypothalamic/Pituitary Disease) *Metyrapone Stimulation Test*: - *Metyrapone* Blocks last step of Cortisol Synthesis (*11ß-Hydroxylase*) (*11-Deoxycortisol → Cortisol*) Normal Response: - ↓Cortisol - ↑ACTH & ↑11-Deoxycortisol 1° Adrenal Insufficiency: - ↑ACTH - ↓11-Deoxycortisol 2°/3° Adrenal Insufficiency: - ↓ACTH - ↓11-Deoxycortisol

*Hashimoto Thyroiditis* - Defect: - Pathology - Association: - Findings: - Histological Findings:

Defect: - Most Common *Hypothyroidism* in Iodine-Sufficient Regions Pathology: - *Autoimmune* Disorder → *Anti-Thyroid Peroxidase* Antibody → *Anti-Microsomal* Antibody → *Anti-Thyroglobulin* Antibody - *HLA DR3* & *HLA DR5* Associated with: - *Non-Hodgkin B-Cell Lymphoma* Findings: - Early Hyperthyroid (Follicular Rupture) - Then *Hypothyroid* - *Nontender* Thyroid Histologic Findings: - *Hürthle Cells* - Lymphoid Aggregates with *Germinal Centers*

*Riedel Thyroiditis* - Defect: - Association: - Findings:

Defect: - Thyroid Replaced by *Fibrous Tissue* - *Inflammatory Infiltrate* - *Fibrosis Extends* to Local Structure - Mimics **Anaplastic Carcinoma** - *1⁄3* are *Hypothyroid* Associated with: - *IgG4-Related Systemic Disease* Findings: - *Fixed* - *Rock-Hard* - *Nontender Goiter*

*Glucagonoma* - Defect: - Symptoms: - Association: - Treatment:

Defect: - Tumor of *Pancreatic α Cells* - Overproduction of *Glucagon* - *Hyperglycemia* Symptoms: - **Necrolytic Migratory Erythema** of Skin - *Diabetes* Association: - *MEN 1* (Pancreatic Tumor) Treatment: - *Octreotide* (Somatostatin) - Surgery

*Insulinoma* - Defect: - Symptoms: - Labs: - Association: - Treatment:

Defect: - Tumor of *Pancreatic β Cells* - Overproduction of *Insulin* - *Hypoglycemia* Symptoms: - *Whipple Triad*: → Low Blood Glucose → Symptoms of Hypoglycemia → Resolution of Symptoms after Normalization of Glucose Levels *First Symptoms of Hypoglycemia*: - Sympathetic Hyperarousal (*Epinephrine* Compensation: ↑HR, Sweating) *Later Symptoms of Hypoglycemia*: - CNS Symptoms: - Lethargy, Altered Mental Status, Coma Labs: - *↑C-Peptide* (vs Exogenous Insulin) Association: - *MEN 1* (Pancreatic Tumor) Treatment: - *Octreotide* (Somatostatin) - Surgery

*Somatostatinoma* - Defect: - Symptoms: - Treatment:

Defect: - Tumor of *Pancreatic δ Cells* - Overproduction of *Somatostatin* - *↓Insulin* - *↓Glucagon* - *↓Cholecystokinin (CCK)* - *↓Secretin* - *↓Gastric Inhibitory Peptide (GIP)* - *↓Gastrin* Symptoms: - *Diabetes*/Glucose Intolerance - *Steatorrhea* - *Gallstones* - Achlorhydria (Absence of HCl) Treatment: - Surgery - Somatostatin Analog (*Octreotide*) for Symptom Control

*Hypopituitarism* - Defect: - Treatment: - Causes:

Defect: - Undersecretion of *Pituitary Hormones* Treatment: - *Hormone Replacement Therapy* → Corticosteroids → Thyroxine → Sex Steroids → Human Growth Hormone Causes: *Nonsecreting Pituitary Adenoma* *Craniopharyngioma* (Rathke's Pouch) *Brain Injury* *Radiation* *Sheehan Syndrome* - Ischemic Infarct of Pituitary Following Postpartum Bleeding - Pregnancy-Induced Pituitary Growth - ↑Susceptibility to Hypoperfusion - Failure to *Lactate* - Absent Menstruation - Cold Intolerance *Empty Sella Syndrome* - Atrophy/Compression of Pituitary (Lies in In Sella Turcica) - Common in Obese Women *Pituitary Apoplexy* - Sudden *Hemorrhage* of Pituitary - Often with an Existing Pituitary Adenoma - Sudden Onset Severe HA - Bitemporal Hemianopia - Diplopia due to CN III Palsy - Hypopituitarism

*2º Adrenal Insufficiency* - Defect: - Symptoms:

Defect: - ↓*Pituitary* ACTH Production - Often part of *Panhypopituitarism* Symptoms: - *Aldosterone Synthesis Preserved* due to *Intact RAAS* - No Hypotension - No Hyperkalemia - No Metabolic Acidosis - *No Skin/Mucosal Hyperpigmentation* (↓ACTH, ↓MSH)

*Toxic Multinodular Goiter* - Defect: - Histology

Defect: - *Hyperfunctioning* Follicular Cells - Work *Independently of TSH* (TSH Receptor Mutation in 60%) - *↑T3/T4* - *Hyperthyroidism* Association: - *Hot Nodules* (Takes up Radiation) → *Not Malignant* Histology: - Focal Patches of Hyperfunctioning Follicular Cells *Distended with Colloid*

*Thyroid Cancer* - Diagnosis: - Treatment: - Surgery Complications - Types:

Diagnosis: - With *Fine Needle Aspiration* Treatment: - Treated with *Thyroidectomy* Surgery Complications: - *Hoarseness* (Recurrent Laryngeal Nerve Damage) - *Hypocalcemia* (Removal of Parathyroid Glands) Types: → Papillary Carcinoma → Follicular Carcinoma → Medullary Carcinoma → Anaplastic Carcinoma → Lymphoma

Congenital Adrenal Hyperplasia: *11β-Hydroxylase*

Mineralocorticoids: - ↓Aldosterone - ↑11-Deoxycorticosterone (Results in ↑BP) Cortisol: ↓ Sex Hormones: ↑ BP: ↑ K+: ↓ Labs: - ↓Renin Activity Presentation: - XX: *Virilization/Masculinization*

Congenital Adrenal Hyperplasia: *17α-Hydroxylase*:

Mineralocorticoids: ↑ Cortisol: ↓ Sex Hormones: ↓ BP: ↑ K+: ↓ Labs: - ↓Androstenedione Presentation: XY: - *Ambiguous Genetalia* - *Undescended Testes* XX: - *Lack 2º Sexual Development* (↓Testosterone = ↓Estrogen [Aromatase])

Congenital Adrenal Hyperplasia: *21-Hydroxylase*:

Mineralocorticoids: ↓ Cortisol: ↓ Sex Hormones: ↑ BP: ↓ K+: ↑ Labs: - ↑Renin Activity - ↑17-Hyroxyprogesterone Presentation: - *Salt Wasting, Dehydration, Vomiting* - XY: *Precocious Puberty* - XX: *Virilization/Masculinization*

*Calcium Homeostasis*

Plasma Ca2+ Exists in 3 Forms: → *Ionized/Free* (45%, Active Form) → Bound to *Albumin* (40%) → Bound to *Anions* (15%) *Acidosis → Hypercalcemia* *Alkalosis → Hypocalcemia*

*Posterior Pituitary (Neurohypophysis)* - Secretes:

Produced by: - *Hypothalamus* Storage/Secretion: - *Vasopressin (ADH)* - *Oxytocin* - Both Made in Hypothalamus: ADH: *Supraoptic Nucleus* Oxytocin: *Paraventricular Nucleus* - Transported to Posterior Pituitary via *Neurophysins* (Carrier Proteins)

*Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH)* - *Causes*: - Findings: - *Body's Response*: -Complications: - Treatment:

SIADH Causes: - *Small Cell Lung Cancer* (Ectopic ADH) - *Cyclophosphamide* - CNS Disorders/Head Trauma Findings: - Excessive ADH - Excessive Free Water Retention - Hyponatremia - Dilute Serum - Concentrated Urine - Urine Osmolality > Serum Osmolality Body's Responds to Water Retention: - ↓Aldosterone - ↑ANP/BNP - ↑Urinary Na+ Secretion - Normalize Volume/ECF Volume - **Euvolemic Hyponatremia** Complications of *Hyponatremia*: - *Cerebral Edema* - Seizures - Correct Hyponatremia *Slowly* to Avoid *Osmotic Demyelination Syndrome* (Central Pontine Myelinolysis) - *"Low to High, your Pons will Die"* Treatment: - Fluid Restriction - Salt Tablets - IV Hypertonic Saline - Diuretics - *ADH Antagonists*: → *Conivaptan* → *Tolvaptan* → *Demeclocycline*

*Anterior Pituitary (Adenohypophysis)* - Secretes:

Secretes: - *FSH* - *LH* - *ACTH* - *TSH* - *Prolactin* - *GH* - *Melanotropin (MSH)* secreted from "Intermediate Lobe" of Pituitary - *ACTH & MSH* are Derivatives of *Proopiomelanocortin (POMC)* → *Acidophils*: (*"GPA"*) - Stain *Pink* - GH, Prolactin → *Basophils* - Stain *Blue* - LH, FSH, ACTH, TSH *α-subunit*: - Hormone Subunit common to: *hCG*, LH, FSH, TSH *β-subunit*: - Determines Hormone Specificity.

*Hypothyroidism*: - Signs/Symptoms: - Lab Findings:

Signs/Symptoms: → Cold Intolerance → *Weight Grain, ↓Appetite* → Hypoactivity, Fatigue, Depressed → Constipation → ↓Reflexes → Myopathy (Weak Muscles, ***↑CK***) → *Myxedema* (Facial/Periorbital) → Dry, Cool Skin; Coarse, Brittle Hair → Bradycardia, Dyspnea on Exertion → *Menstrual Irregularity* (*↓T3/T4, ↑TRH, ↑Prolactin, Block GnRH*) Lab Findings: - ↓Free T3/T4 - ↑TSH (if 1º) - *Hypercholesterolemia* (Due to ↓LDL Receptor Expression)

*Hyperthyroidism* - Signs/Symptoms: - Lab Findings:

Signs/Symptoms: → Heat Intolerance → *Weight Loss, ↑Appetite* → Hyperactivity, Anxiety, Hand Tremor → Diarrhea → ↑Reflexes → Myopathy (Weak Muscles, *Normal CK*) → Pretribial Myxedema (Graves Disease) → Warm, Moist Skin; Fine Hair → Chest Pain, Palpitations, Arrhythmia (↑Sensitivity of ß-Adrenergic Receptors) → *Menstrual Irregularity* (↑T3/T4, ↑SHBG, Binds/↓ Sex Hormones) Lab Findings: - ↑Free or Total T3/T4 - ↓TSH (if 1º) - *Hypocholesterolemia* (Due to ↑LDL Receptor Expression)

Causes of *Goiter*

Smooth/Diffuse: → Iodine Deficiency → TSH-Secreting Pituitary Adenoma → Graves Disease → Hashimoto Thyroiditis → Subacute Granulomatous Thyroiditis (de Quervain) → Riedel Thyroiditis Nodular: → Thyroid Cyst → Toxic Multinodular Goiter → Thyroid Adenoma (Benign) → Thyroid Cancer

*Parathyroid Hormone (PTH)* - Source: - Function: - Regulation

Source: - *Chief Cells* of Parathyroid Gland Function: - ↑Bone Resorption of Ca2+ & PO4(3)− - ↑Kidney Reabsorption of Ca2+ in DCT - ↓Kidney Reabsorption of PO4(3) in PCT - ↑1,25-(OH)2 D3 (Calcitriol) by Stimulating Kidney 1α-Hydroxylase in PCT PTH Causes: - ↑Serum Ca2+ - ↓Serum PO4(3)- - ↑Urine PO4(3)- - ↑Urine *cAMP* (Cyclic-Adenosine Mono*Phosphate*) - PTH has Receptors on Osteoblasts (Not Osteoclasts) - PTH induces *Osteoblasts* - *RANK-L from Osteoblasts* Binds *RANK on Osteoclasts* - Stimulates Osteoclasts & ↑Ca2+ - *PTH-Related Peptide* (*PTHrP*) functions like PTH & is Increased in Malignancies → *Lung Squamous Cell Carcinoma* → *Renal Cell Carcinoma* Regulation: - ↓Serum Ca2+ → ↑PTH Secretion - ↑Serum PO4(3)− → ↑PTH Secretion - ↓Serum Mg2+ → ↑PTH Secretion - *↓↓Serum Mg2+ → ↓PTH Secretion* Common Causes of ↓Mg2+: - Diarrhea - Diuretics - Aminoglycosides - Alcohol Abuse

*Vitamin D* - Source: - Function: - Regulation: - Deficiency: - Cause of Deficiency:

Source: - *D3* from Skin Sun Exposure & Diet - *D2* from Diet - D2/D3 → *25-OH Vitamin D* in *Liver* via [25-Hydroxylase] - 25-OH Vitamin D → *1,25-(OH)2 Vitamin D* in *Kidney* via [1α-Hydroxylase] Note: - 25-OH Vitamin D → 1,25-(OH)2 Vitamin D - *REQUIRES PTH* for [1α-Hydroxylase] Activation → *No PTH* → *No 1,25-(OH)2 Vitamin D* Function: - ↑Absorption of Dietary *Ca2+* & *PO4(3)−* - Enhances Bone Mineralization Regulation: - ↑PTH, ↓Ca2+, ↓PO4(3)− → *↑1,25-(OH)2 Production* *PTH* leads to: - *↑Ca2+* & *↓PO4(3)−* in *Kidney* *1,25-(OH)2 D3* leads to: - *↑Ca2+* & *↑PO4(3)−* in *Gut* Deficiency: → *Rickets* in Kids → *Osteomalacia* in Adults Cause of Deficiency: - Malabsorption - Poor Diet - ↓Sunlight - Chronic Kidney Failure

*Insulin* - Source: - Synthesis:

Source: - *Pancreatic β Cells* Synthesis: - *Preproinsulin* (Synthesized in *RER*) → Cleavage of "Presignal" → *Proinsulin* (In Secretory Granule) → Cleavage of Proinsulin → Equal *Insulin & C-Peptide* Exocytosed → *Insulin* (Active) & *C-Peptide* (Inactive) - Insulin & C-Peptide Both Increased in: → *Insulinoma* → *Sulfonylurea* - Only Insulin, Lacking C-Peptide: → *Exogenous Insulin*

*Glucagon*: - Source: - Function: - Secretion: - Inhibition:

Source: - *α Cells* of Pancreas Function: - *Glycogenolysis* - *Gluconeogenesis* - *Lipolysis* - *Ketogenesis* Secreted due to: - *Hypoglycemia* Inhibited by: - *Hyperglycemia* → *Insulin* → *Somatostatin*

*Cortisol*: - Source: - Function: - Regulation:

Source: - Adrenal Cortex: Zona Fasciculata - Bound to Corticosteroid-Binding Globulin Function: *"A BIG FIB"* *↑Appetite* *↑Blood Pressure*: - Upregulates α1-Receptors on Arterioles *↑Insulin Resistance* (*Diabetogenic*) *↑Gluconeogenesis/Glycogenolysis*, Lipolysis, Proteolysis *↓Fibroblast Activity* - Poor Wound Healing - ↓Connective Tissue - ↓Collagen Synthesis - ↑Striae *↓Inflammatory & Immune Responses*: - Inhibits Phospholipase A2 - Inhibits Leukotrienes - Inhibits Prostaglandins - Inhibits WBC Adhesion → Neutrophilia - Blocks Mast Cell Histamine Release - Eosinopenia (↓) - Blocks IL-2 Production (T-Cells) *↓Bone Formation* - ↓Osteoblast - *Exogenous Corticosteroids* can Cause Reactivation of *TB & Candidiasis* - Due to Inhibition of *IL-2* Production - *Chronic Stress* → ↑↑Cortisol Secretion

*Growth Hormone (Somatotropin)* - Source: - Function: - Side Effects: - ↑Secretion: - ↓Secretion: - Excess GH:

Source: - Anterior Pituitary - Released in *Pulses* due to GHRH Function: → Functions thru *IGF-1* (*Somatomedin C*) → Secreted by *Liver* - *Linear Growth* - *Muscle Mass* Side Effects: - *↑Insulin Resistance* (*Diabetogenic*) - Organmegaly (*Heart Hypertrophy*) ↑GH Secretion: → *Exercise* → *Sleep* → *Puberty* → *Hypoglycemia* → *Arginine* (AA) ↓GH Secretion: → *Glucose* → *Somatostatin* (IGF-1 ⊖ Feedback) ↑↑GH (Pituitary Adenoma) can cause: → *Acromegaly* (Adults) → *Gigantism* (Children) - Treatment: *Octreotide* (Somatostatin)

*Prolactin* - Source: - Function: - Regulation:

Source: - Secreted by Anterior Pituitary - Structurally Homologous to GH Function: - Stimulates *Milk Production* in Breast - Inhibits Ovulation in Females & Spermatogenesis in Males by *Inhibiting GnRH* Synthesis & Release - Excessive Prolactin is associated with ↓Libido Regulation: - Prolactin Secretion from Anterior Pituitary is *Inhibited by Dopamine* from Tuberoinfundibular Pathway of Hypothalamus - Prolactin in turn Inhibits its own Secretion by ↑Dopamine Synthesis & Secretion from Hypothalamus. - *TRH causes ↑Prolactin* (1° or 2° Hypothyroidism) - *Dopamine Agonists* (*Bromocriptine*) Inhibits Prolactin & is used to treat Prolactinoma - *Dopamine Antagonists* (*Antipsychotics*) and Estrogens (OCPs, Pregnancy) Stimulate Prolactin Secretion. - *Progesterone* inhibits Milk Let Down until after Delivery

*Antidiuretic Hormone (ADH)* - Source: - Function: - Regulation:

Source: - Synthesized in Hypothalamus (*Supraoptic Nucleus*) - Stored/Secreted by Posterior Pituitary Function: - Regulates *Serum Osmolarity* (*V2*-Receptors) - Regulates *Blood Pressure* (*V1*-Receptors) - 1º Function is Serum Osmolarity via Regulation of *Aquaporin Channel* Insertion in *Principal Cells* of Renal Collecting Duct → ADH: ↓Serum Osmolarity → ADH: ↑Urine Osmolarity - ↓ADH in *Central DI* - Normal/↑ADH in *Nephrogenic DI* - Nephrogenic DI can be caused by *Mutation in V2-Receptor* - *Desmopressin Acetate* (ADH Analog) is a treatment for *Central DI* Regulation: - Osmoreceptors in Hypothalamus (1°) - Hypovolemia

*Calcitonin* - Source: - Function: - Regulation

Source: - Thyroid *Parafollicular (C) Cells* Function: - "Calcitonin Tones Down Ca2+" - ↓Ca2+ - ↓Bone Resorption for Ca2+ - Calcitonin Opposes Actions of PTH Regulation: - ↑Serum Ca2+ → Calcitonin Secretion

*Synthesis* & Secretion of Thyroid Hormone

Thyroid Hormone Synthesis requires: → *Iodine* → *Tyrosine* → I- is transported using *Na/I Symporter* → I- is *Oxidized* by *Thyroid Peroxidase* to I(2) → I(2) is incorporated into *Tyrosine* on Thyroglobulin (TG) → I(2) goes through *Organification* by *Thyroid Peroxidase* to form DIT/MIT → *Coupling Rxn* of MIT/DIT to T4/T3 by *Thyroid Peroxidase* (DIT + DIT = T4; DIT + MIT = T3) → Endocytosis of TG with attached T3/T4/MIT/DIT → Proteases Remove T3/T4 from TG, MIT, DIT → Free Hormones T3/T4 Released → TG, MIT, DIT Recycled

*Conn Syndrome*:

→ *1º Hyperaldosteronism* ↑Aldosterone - HTN/Hypernatremic - Hypokalemia - Alkalosis

*Addison Disease*

→ *Chronic 1º Adrenal Insufficiency* ↓Aldosterone - Hypotension/Hyponatremic - Hyperkalemia - Metabolic Acidosis ↓Cortisol ↑ACTH (↑MSH) - Skin Hyperpigmentation

- *Thyroid Follicular Cells* are derived from

→ *Endoderm*

In *Sheehan Syndrome*, which Essential Hormones must be Replaced Immediately?

→ *Glucocorticoids (Cortisol)* → *Thyroid Hormone*

*Other Hypothyroidism Causes* - Drugs:

→ *Iodine Deficiency* → *Wolff-Chaikoff Effect* (Thyroid Gland Downregulation in Response to ↑Iodide) Goitrogens: → *Amiodarone* → *Lithium*

What 2 Drugs can cause *Nephrogenic Diabetes Insipidus*:

→ *Lithium* → *Demeclocycline* (ADH Antagonist)

*Adrenal Cortex* is derived from:

→ *Mesoderm*

*Adrenal Medulla* with it's *Chromaffin Cells* are derived from:

→ *Neural Crest Cells* of Ectoderm

- *Parafollicular C Cells of Thyroid* are derived from

→ *Neural Crest Cells* of Ectoderm

*Posterior Pituitary (Neurohypophysis)* - Derived from:

→ *Neuroectoderm*

*Diabetes Mellitus * - Chronic Complications: *Nonenzymatic Glycation*

→ *Nonenzymatic Glycation*: *Small Vessel Disease* (BM Thickening) → *Retinopathy* - Hemorrhage - Exudates - Microaneurysms - Vessel Proliferation → *Neuropathy* → *Nephropathy* - Arteriolosclerosis & HTN leading to Chronic Renal Failure - Nodular Glomerulosclerosis - Kimmelstiel-Wilson Nodules - Progressive Proteinuria; - ACE Inhibitors are Renoprotective *Large Vessel Atherosclerosis* → *Abdominal Aorta*: Aneurysm, Emboli → *Coronary Arteries*: Angina, MI → *Popliteal Artery*: Gangrene, Limb Loss → *Carotid Arteries*: Embolic Stroke

*Anterior Pituitary (Adenohypophysis)* - Derived from:

→ *Oral Ectoderm* (*Rathke Pouch*)

*Diabetes Mellitus* - Chronic Complications: *Osmotic Damage*

→ *Osmotic Damage* - *Glucose → Sorbitol* (Aldose Reductase) - No Sorbitol → Fructose (Sorbitol Dehydrogenase) - *Sorbitol Accumulation in Organs* - *Draws Water* - Effects Schwann Cells → *Neuropathy* - Effects Lens → *Cataracts*

Signaling Pathway of Endocrine Hormone: *Intracellular Receptors*

→ *Progesterone* → *Estrogen* → *Testosterone* → *Cortisol* → *Aldosterone* → *T3/T4* → *Vitamin D*