262 OSMOSISORG Ltt RNA bucy ENDOCRINE ANATOMY & PHYSIOLOGY Poser aut Urs us ENDOCRINE GLANDS + Sectete hormones directly into bloodstream (exocrine glands use ducts) + Maintain homeostasis by controling variables such as body temperature, uid balance + Especially with negative feedback mechanisms HORMONES * Can be classified as steroidsinon-steroids Steroid hormones + Derived from cholesterol: produced in adrenal glands, gonads (testesfovares) + Hydrophobichon-polar—» travel through bloodstream with transport protein, diffuse across target cell phospholipid membrane Non-steroid hormones + Derived from peptidesiproteins or single amino acids + Peptidic hormones are hydrophilic -+ bind surface receptor proteins instead of passing through target cell membrane + Amino acid hormones derived from tyrosine: generally hydrophilic (e.g adrenalinelepinephrine and noradreneline! norepinephrine), apart from thyroid hormones ind-phystology ERO! PEPTIDE HORMONES HORMONES LiwvoroPHogic __LHYDROPHILIC BO|| O Figure 314 Steroid hormones diffuse across the target cell membrane and bind to an intracellular receptor. Peptide hormones bind to a cell surface receptor. Both methods result in changes in gene expression, HORMONE SECRETION & REGULATION Paracrine signaling + Effects of hormones released by nearby cells; eg. glucagon —» activates alpha calls, inhibits beta cells ‘Sympathetic nervous system + Epinephrinelnorepinephrine alter secretion depending on adrenergic receptor type: + e482: activates beta cells, Parasympathetic nervous system + Acetylcholine activates alpha cells and beta cells via M3 receptorsChapter 31 Endocrine Physiology: Endocrine Anatomy & Physiology GLAND LOCATIONS & FUNCTIONS + Endocrine glands scattered throughout body Hypothalamus * Located at base of brain + Hypothalamus, brain work closely to make hormones that control other endocrine glands + Made up of several nuclei (neuron clusters) which secrete hormones, Pituitary gland * Located just below brain; physically connected to hypothalamus by pituitary stalk (infundibulum) + Made up of anterior, posterior lobe + Anterior pituitary: AKA adenohypophysis = Made of glandular tissue + Receives stimulatory inhibitory hormones from hypothalamus via hypothalamo-hypophyseal-portal system + Posterior pituitary: AKA neurohypophysis, «= Made of axons from hypothalamic supraoptic, paraventricular nuclei += Receives hormones directly from hypothalamus + Instead of producing own hormones, posterior pituitary stores hormones for later release += Herring bodies: axon dilations which store hormones + Hormones include antidiuretic hormone (ADH\vasopressin), oxytocin ADH signals: 1 blood osmolarity, | blood volume (ADH retains water from urine, constricts blood vessels — negative feedback) * Oxytocin signals: childbirth (tates cervix, stimulates uterine contractions), breastfeeding (contracts breast calls) social interaction, orgasm + Stimulatory pituitary hormones * Thyrotropin releasing hormone (TRH) pituitary secretes thyroid-stimulating hormone (TSH) = thyroid produces thyroid hormones » Corticotropin releasing hormone (CRH): pituitary secretes adrenocorticotropic hormone (ACTH) ~+ adrenal glands produce cortisol * Gonadotropin releasing hormone (GnRH: pituitary secretes gonadotropins, eg folicle-stimulating hormone (FS, luteinizing hormone (LH) + gonads produce gametes (sperm for testes, oocytes for ovaries), sex hormones ftestosterone, estrogen, progesterone) * Growth hormone releasing hormone (GHRH): pituitary secretes growth hormone — growth of long bones, tissues in body + Inhibitory pituitary hormones » Growth hormone inhibiting hormone (GHiFsomatostatin): pituitary secretes lessino growth hormone PARAVENTRICULAR NUCLEUS suPRAOPTIC. evRONS ‘TWN STALK POSTERIOR LOBE. (x08) Figure 31.2 Endocrine glands’ location and the relationship between the hypothalamus and the the pituitary gland’s two lobes. OSMOSIS.ORG 263+ Prolactin inhibiting hormone (dopamine): pituitary secretes lessho prolactin (no milks produced whenever not breastfeeding) Pineal gland + Located behind hypothalamus, pituitary gland * Contains pinealocytes which synthesize melatonin © Melatonin mostly secreted during night, regulates body's circadian rhythm (body clock) Thyroid gland + Located at front of neck * Left right lobe + Made of thousands of follicles which synthesize triiodothyronine (T,), thyroxine ™ vin the cell T, +7, +, +1 basal metabolic rate + Parafollicular cells (C-cells) between follicles secrete calcitonin + Two parathyroid glands on back of each thyroid lobe (four in total} secrete parathyroid hormone * Calcitonin, parathyroid hormone work similarly * Control calcium, phosphate, bone metabolism + Regulated by blood calcium levels THYROID GLAND FOLLICLES v "eooriONe (,)_ PARAFOLLIGULAR CELLS ‘THYROXINE (T.) y cavcrown Figure 31.4 Follicular cells of the thyroid gland synthesize T,, T, parafolicular cells secrete calcitonin 264 OSMOSISORGChapter 31 Endocrine Physiology: Endocrine Anatomy & Physiology » POSTERIOR 4 THYROID GLAND S \] PARATHYROID GLANDS HW \\ ll, 9} Wl i PARATHYROID HORMONE. Figure 315 The parathyroid glands are found on the back of the thyroid. They secrete parathyroid hormone. Adrenal glands + Two glands situated retroperitoneally inside renal fascia, each surrounded by fibrous capsule: sit on top of kidneys += Connective tissue separates them from kidney, renal fascia from diaphragm + One ofthe most vascularized tissues + Differin shape (right shaped as pyramid left shaped as crescent moon) + Outer layer (cortex) surrounding a core (medulia) + Medulla: neuroectodermal origin: secretes catecholamines (e, adrenaline, noradrenaline) during “fight or flight” situations +t blood pressure, f cardiac output. bronchial dilation, t glyeogenolysis + Cortex: makes up 80% of gland, mesodermal origin, secretes adrenocortical steroid hormones += Three zones: zona glomerulosa (makes mmineralocorticoids—e.g, aldosterone), zona fasciculata (makes glucocorticoids), zona reticularis (makes sex hormone precursors) + Aldosterone: regulates extracellular fluid volume, potassium homeostasis involved in renin-angiotensin- aldosterone system (RAS); f renal ‘water and sodium reabsorption, f renal potassium excretion ->t blood pressure «Cortisol: integral to stress response; also has metabolic, antiinflammatory, immunosuppressive, vascular effects; regulated via hypothalamic-pituitary- adrenal (HPA) axis * Androgens: adrenals only source of andragens in biolagically-fernale individuals; effects include 1 libido, pubic hair development, sebaceous gland hypertrophy; minor role in biologically male adults ENDOCRINE PANCREAS * Located behind stomach + Three sections Head, body, tail ‘+ Has both endocrine, exocrine functions * Contains hormone-producing cell clusters + Islets of Langerhans (1-2% of pancreas) * Produce hormones secreted directly into bloodstream that regulate blood glucose Cell types + Alpha (a) cells. * 15-20% of total islet cells » Produce glucagon * [blood glucose — glucagon secreted + hepatic aycogenalysis and gluconeogenesis + glucose released into bloodstream + Bete (8) cells » 65-80% of total slat cells » Produce insulin, amin » {blood sugar — insulin secreted + anabolic functions: promotes glucose entry into cells, t glycogen synthesis, lipolysis + Gamma {| cellPP cells + 3.5% of total islet cells +» Produce pancreatic polypeptide » Secretion stimulated by meals high in protein, hypoglycemia, physical activity, fasting inhibits pancreatic exocrine enzymes) and endocrine (insulin) activity + Delta (6) cells »3-10% of total islet cells * Produce somatostatin += Paracrine function of suppressing both insulin and glucagon + Epsilon (¢ cells + € 1% of total islet cols * Produce ghrelin » Funetians in appetite stimulation OSMOSIS.ORG 265ALposrenone ADRENAL GLANDS Jo zona LORERULOsA 7040, CORTISOL kioNeY scan ie oN neTicluans CATECHOLAMINES ouvonsene RecuRcons Figure 31.6 Location of the adrenal glands and the hormones secreted by the cortex, medulla, PANCREAS ‘® ENDOCRINE Usecretes INSULIN & a GLUCAGON * EXOCRINE. CHeLes with DIGESTION Figure 347 The pancreas has both endocrine and exocrine functions. It has hormone-producing Clusters of cells called Islets of Langerhans. 266 OSMOSISORGChapter 31 Endocrine Physiology: Endocrine Anatomy & Physiology MATJOR HORMONES AND THEIR FUNCTIONS cry CO eal FUNCTION Dy cd Paty DL 1 blood aeose, intammatory response {tine sci, ine assum SSM testosterone _ | ome | OSMOSIS.ORG 267268 OSMOSISORG Ls) MV ala [e Ute) [ty —— GENERALLY, WHAT ARE THEY? ——— + Pituitary gland: AKA hypophyseal gland! hypophysis + Connected to hypothalamus via pituitary stalk (infundibulum) which controls pituitary secretory actions + Consists of two embryologically, functionally different parts that secrete different hormones ANTERIOR PITUITARY (ADENOHYPOPHYSIS) * Connects to hypothalamus via blood vessels (hypophyseal portal system) + Hypothalamus produces releasing hormones —» pituitary secretes tropic hormones that regulate target tissues Corticotropin-releasing hormone (CRH) + Adrenocorticotropic hormone (ACTH) —> adrenal medulla Gonadotropin-releasing hormone (GnRH) + Luteinizing hormone (LH), follicle stimulating hormone (FSH) — ovaries, testes Growth hormone releasing hormone (GHRH) + Stimulates release of somatotropin/ growth hormone (GH) — various tissues throughout body Thyrotropin-releasing hormone (TRH) stimulating hormone — thyroid Prolactin (PL) + Acts on breasts lactogenesis) + Hypothalamus inhibits prolactin production via dopamine * TRH, estrogen, progesterone, oxytocin, stimulate prolactin POSTERIOR PITUITARY (NEUROHYPOPHYSIS) + Reoresents an extension of hypothalamus + Does not secrete its own hormones + Stores releases neufohormones synthesized in hypothalamus \Vasopressin/antidiuretic hormone (ADH) + Acts on kidney tubules, arterioles Oxytocin + Acts on uterus, breasts,Chapter 32 Endocrine Physiology: Pituitary Hormones ADRENOCORTICOTROPIC HORMONE (ACTH) osms.it/adrenocorticotropic—hormone + Hormone secreted by anterior pituitary ‘STIMULATION OF ACTH RELEASE coticotopic calls + Corticatopin releasing hormone (CRH) + Main action of ACTH involves stimulating secreted by hypothalamus adrenocortical cels of zone fasciculata = Stress, low blood glucose, low of the adrenal cortexto secrete alucocortcoé levels, increased glucocorticoids (primarily cortisol) sympathetic activity, normal diurnal + Antringlammatory effects rhythm + Increases blood glucose levels + Release of ACTH demonstrates + Increases fat and protein breakdown circadian rhythm affected by suprachiasmatic nucleus low evening SYNTHESIS concentrations, high in morning + Pre-pro-opiomelanocortin (pre-POMC) — proopiomelanocortin (POMC) ACTH RELEASE REGULATION ACTH, gamma lipotropin, beta endorphin, _* ACTH releases regulated by melanocyte-stimulating hormone hypothalamic-pituitary-acrenal axis negative feedback » Hypothalamus releases CRH + CRH stimulates pituitary to release ACTH + ACTH stimulates adrenal cortex to secrete cortisol +t cortisol inhibits hypothalamic release of CRH —> |CRH decreases ACTH secretion —+ closed loop PRE-ROOPGMELANOCORTIN (gre POMC) — ACTH SIGNALING PATHWAY * ACTH binds to ACTH receptor on adrenal cortex adrenocorticotropic cells, primarily zona fasciculata also expressed in skin, ProemoneLconTIN both white, brown adipocytes + ACTH receptoris a seven-memibrane- spanning G-coupled receptor + ACTH binds to receptor > activates G, protein ~r a subunit released > activates adenylate cyclase + CAMP —+ activates protein kinase A —+ phosphorylation cascade + transcription facto activation —> effects Figure 321 Synthesis of ACTH in the anterior pituitary. Cortictropin releasing hormone (CRH} stimulates the cel to release ACTH, OSMOSIS.ORG 269HYPOTHALAMUS. Figure 32.3 ACTH receptors are found on. adrenocortical cells in the zona fasciculata of the adrenal cortex, as well as on melanocytes inthe skin. Figure 32.2 The negative feedback loop which regulates ACTH release, 270 OSMOSISORGChapter 32 Endocrine Physiology: Pituitary Hormones GROWTH HORMONE (GH) + AKA somatotropin + Peptide hormone secreted by somatotropic calls of anterior pituitary = Regulates tissue growth + Released in pulsatile manner every two hours; peaks one hour after falling asleep REGULATION OF SECRETION Induction of GH release + Hypoglycemia, t estrogen, testosterone (puberty), stress (eg, trauma, fever), exercise, sleep stages Il, IV Three negative feedback loops + | GH stimulates hypothalamus to release GHRH — | GHRH stimulates ptuitary to release GH — 1 GH inhibits release of GHRH — absence of GHRH inhibits GH release — closed loop + | GH stimulates somatomedins production in the liver, bones, muscles —» somatomedins inhibit GH release + | GH and somatomedins stimulate somatostatin production in hypothalamus + somatostatin inhibits GH release GH SIGNALING PATHWAY + Growth hormone receptor (GHR) belongs to cytokine receptor family + To activate intracellular signaling, GH must bind to two GH receptors -» dimerization of GHR + GH binds to receptor -+ conformational change —+ key tyrosine residue phosphorylation -+ activation of tyrosine kinase JAK2 —» STATS, Src family kinases, insulin receptor substrate (IRSs} signaling ‘molecule activation — gene transcription, effects THA U\ GNRH | + = | SOMATOSTATIN o + f eZee Sy (somaTomenin) Figure 32.4 The three negative feedback loops that regulate GH secretion, each highlighted in a different colour. GH ‘and somatomedin together stimulate somatostatin production in the hypothalamus, which inhibits GH release. EFFECTS OF GH + Primary effect of GH is cell metabolism stimulation, growth, division ct effects + Anti-insulin-like effects + Carbohydrates: | blood glucose levels » Stimulates gluconeogenesis, glycogenolysis in liver + Increases tissue insulin resistance + Fats: 1 fatty acids in blood + Stimulates adipose tissue lipolysis Indirect effect + Insulin-like effects through insulin-thke ‘growth factors (e.g, somatomedins like IGF-1) + Stimulates cell growth, division, and increased linear growth THYROID-STIMULATING HORMONE (TSH) osms.it/thyrotd-hormone + AKA thyrotropin * Glycoprotein hormone secreted by pituitary gland + Main action of TSH involves stimulating thyroid gland growth, thyroid hormone synthesis, release ‘STIMULATION OF TSH RELEASE + Thyrotropin-releasing hormone (TRH) secreted by hypothalamus = Low T,,T, blood levels. = Decreased metabolism * Cold stress = Conditions that increase ATP demand REGULATION OF SECRETION + TRH secreted by hypothalamus, stimulates pituitary thyrotropic cells to release TSH + Thyroid hormones, specifically T,. down- regulate TRH receptors on thyrottopic cals, inhibiting TSH secretion + TSH release, thyroid hormone is regulated by negative feedback loop = Hypothalamus releases TRH > TRH stimulates pituitary to release TSH TSH travels to thyroid flicle stimulates thyroid hormones synthesis secretion ~» thyroid hormones inhibit both TRH, TSH release — absence ‘of TRH, TSH inhibits further thyroid hormone secretion -» closed loop TSH SIGNALING PATHWAY + TSH binds TSH receptor primarily found on ‘thyroid gland follicular cells * Also found on adipose tissue, fibroblasts + TSH receptors integral membrane receptor coupled with G, protein + TSH binds to receptor — activates G, protein >a subunit released — activates adenylate cyclase +1 cAMP — activates protein kinase A ~+ phosphorylation cascade —+ transcription factor activation —» effects EFFECTS OF TSH + TSH has two effects on the thyroid gland + Stimulates all the steps in thyroid hormone synthesis, secretion * Trophic effect: increases growth of thyroid glandChapter 32 Endocrine Physiology: Pituitary Hormones THYROID HORMONE + Glycoprotein hormones T, (tiiodothyronine), T, (tetraiodothyronine) secreted by thyroid follicular epithelial cells + Less active form thyroid hormone (T.) is secreted, converted in target tissue into more active form {T,) SYNTHESIS OF THYROID HORMONES Six steps + Thyreglobuln (TS) synthesized in folicular cell rough endoplasmic reticulum (RER), secreted into lumen {callaid) + lodine from blood enters folicular cells on FOLLICULAR FoLLicLe CELL ‘TwyRoID GLAND Fe FOLLICULAR CELL basolateral ide via Na‘/! symport + lodine exits cell on apical side via transporter pendrin + Inside follicle lumen at apical side, iodine oxidized by enzyme thyroid peroxidase (I sl) + |, iodinates TS tyrosyl residues (organification of |), catalyzed by thyroid peroxidase, forms monoiodotyrosine (MIT), ditodotyrosine (DIT) + On TG, two DIT molecules coupled to form T, (faster reaction}: MIT coupled with DIT to form T, -+ TG now contains T, T,, MIT. DIT residues oa TROSYL, RESIDUES ci} MONOIODOTYROSINE DIIODOTYROSINE % DIT + DIT > Ty — MIT + DIT =» Ty om), Figure 32.5 Thyroid hormone synthesis overview. 1. Tayroglobulin (1G) is synthesized in rough endoplasmic reticulum, secreted into colloid. 2. lodine enters cel from blood via Na‘fl symporter, 3. lodine exits cel into colloid via pendrin. 4. lodine is oxidized by thyroid peroxidase, become |2 5. iodinates tyrosy residues on TG, forming monoiodotyrosine (MIT], dtodotyrosine (DIT). 6. Two DITs combine to form Ta; MIT combines with DIT to form Ts, OSMOSIS.ORG 273274 OSMOSISORG THYROID HORMONE SECRETION AND TRANSPORT ‘Thyroid hormone secretion + Thytoid hormones stored in colloid until stimulated for secretion += TSH stimulation — endocytosis of iodinated TG by folcular epithelial cels = TG transportation to basal membrane = TG fuses with lysosome —+ TG hydrolysis, T,, Ty MIT, DIT residue release ~»T, (10%), T, (80%) secreted into circulation + lodide from MIT, DIT residues recycled for next synthesis Transport of thyroid hormones + Once in circulation, mast thyroid hormones travel bound to thyroxine-binding protein (TBP) + Some bound to prealbumin, albumin + Small fraction travels unbound —> physiologically active forms Activation of T4 + 90% of secreted thyroid hormone isin less active T4 form + T, activated in target tissue by Si deiodinase —r removes one atom ofl,» T, gets converted to T, ‘BLOOD VESSEL fh 4 THYROXINE, BINDING. PROTEIN ‘gd & + Starvation inhibits 5'-deiodinase in target tissue, except in brain + lowers O, consumption, basal metabolic rate (MR) REGULATION OF SECRETION Negative feedback loop + Regulated by negative feecback loop in hhypothalamic-pituitary-thyroid axis » Thyrotropin-releasing hormone (TRH) secreted by hypothalamus, stimulates thyrotropic cells of pituitary to release thyroid-stimulating hormone (TSH) Effects of TSH on thyroid gland + Two effects » Stimulates all steps in thyroid gland synthesis, secretion » Trophic effect: increases thyroid gland growth Other regulatory factors + lodine deficiency + Excessive iodine intake (Wolff-Chalkoft effect) * Inhibits iodine organification + 5'-deiodinase deficiency (eg. starvation) + | TBP synthesis fe. liver failure) * Increases unbound (active) thyroid hormones fraction FOLLICULAR CELL. COLLOID Figure 32.6 Thyroid hormone secretion overview. 1. TG in colloid is endocytosed into folicular cell.2. Lysosome fuses with vesicle; thyroid hormones are cleaved from TG. 3, Hormones are released into blood. 4. In blood, most thyroid hormones travel bound to a protein, thyroxine-binding protein being most common.HYPOTHALAMUS Figure 32.7 ‘The negative feedback loop which regulates thyroid hormone secretion. SIGNALING PATHWAY + Thyroid hormones act on all organ systems + Inside target cell, T, converts to T, -+T, enters nucleus, binds nuclear receptor = T, receptor complex binds DNA, stimulates transcription + translation — protein synthesis + T, stimulates synthesis of Na-K> ATPase, Ca* ATPase, transport proteins, proteotytic, lysosomal enzymes, Bl adrenergic receptors, sructural proteins EFFECTS OF THYROID HORMONE + Key hormone in regulating body ‘metabolism; also important for embryological growth + General effect: all tissues except brain, spleen and gonads =f Na-K-ATPase —> f oxygen consumption —+ 1 basal metabolic rate (BMR), body temperature + Catabolic effect: metabolism of macromolecules * f transport proteins > } glucose absorption from GI tract Chapter 32 Endocrine Physiology: Pituitary Hormones * J catecholamine, glucagon, growth hormone activity -» 1 proteolysis, lipolysis, gluconeogenesis * Cardiovascular system "1 BL adrenergic receptors, Ca” ATPase +1 inotropic (contractility), chronotropic (heart rate) effect +f cardiac output * Central nervous syste {CNS) » Gestational period + CNS development + Adult period — 1 brain activity, attention span, memory * Growth = tosteoblast, osteoclast activity — t bone formation, maturation Figure 32.8 In the target cel, Ts is converted to Ts, which enters the nucleus and binds to a receptor. The receptor complex binds to DNA to stimulate transcription. OSMOSIS.ORG 275NOTES 284 OSMOSISORG Ute} CALCIUM & PHOSPHATE lel le ToC UE tel CALCIUM & PHOSPHATE HOMEOSTASIS Blood calcium level regul * Normal total blood calcium: 8.5-10mgidl + Parathyroid hormone: t calcium level * Vitamin Dt calcium level * Caleitonin: | calcium level Extracellular calcium + Diffusible: can cross cell membranes + Free-ionized calcium (Ca*): involved in cellular processes + neuronal action GENERALLY, WHAT IS IT? potential, muscle contraction, hormone secretion, blood coagulation * Complexed calcium: Ca* ionically bound to other negatively-charged molecules (e,. oxalate, phosphate — electrically-neutral molecules, do not partake in cellular processes) + Non- diffusible: cannot crass cell membranes * Calcium bound to large negatively charged proteins (eg. albumin + protein-aloumin complex too large to cross cell membranes —> not involved in cellular processes) CALCITONIN CALCITONIN STRUCTURE * Polypeptide hormone involved in blood calcium regulation * Not primary calcium regulator, even if thyroid gland removed, remaining regulatory mechanisms able to maintain calcium homeostasis + Produced by thyroid gland’s parafollicular cells (C cells) + Ccells synthesize preprocalcitonin (141 amino acid polypeptide} + successive enzymatic cleavage steps produces procalcitonin —> immature calcitonin (33, ‘amino acids) + mature calcitonin (32 ‘amino acids) + storediteadied for release in secretory granules within C cells CALCITONIN RELEASE * Calcium-sensing receptors on C cells’ surface monitor blood calcium levels —» if calcium drifts above normal range > calcitonin released CALCITONIN ACTION * Lowers blood calcium level Bone + | bone resorption -» | blood calcium Concentration * When attaching to bone matrix osteoclast membranes form multiple aims (ruffled border) —> aids attachment, increases surface area “+ arms secrete acid + assists bone breakdownChapter 35 Endocrine Physiology: Calcium & Phosphate Hormonal Regulation + Calcitonin binds to calcitonin receptor Kidneys ‘on basal osteoclast surface -» G-protein + | calcium, phosphate reabsorption by ‘coupled receptor activation —+ adenylate _principal cells of distal convoluted tubules ‘clase activation + adenosine ‘triphosphate (ATP) converted to 3.5 cyclic AMP (cAMP) + f CAMP levels —> | numberof osteocyte arms formed —> | bone resorption fen PARAFOLLIGULAR CELLS yy J (rc CEUs) ‘THYROID GLAND Figure 35.4 Calcitonin is made and stored in thyroid gland's C cells, NORMALLY .. © osTedcLast BONE RESORPTION V BLOOD CALCIUM asteociast Figure 35.2 When calcitonin binds to its receptor on an osteoclast, it reduces number of ‘osteoclast arms formed, decreasing bone resorption and biood calcium. OSMOSIS.ORG 285286 OSMOSISORG PARATHYROID HORMONE + Primary blood- calcium level regulator PARATHYROID GLANDS: + Hormone produced by parathyroid glands, four pea-sized glands found posterior to thyroid Parathyroid gland chief cells synthesize preproparathyroid hormone (preproPTH} (115 amino acid-long protein chain + contains biologically-active parathyroid hormone segment in N-terminal 34 amino acids) + Within chief cell endoplasmic reticulum, protein chain cleaved by enzyme peptidase (peptidase removes "pre ‘segment — proPTH -» transported to Golgi apparatus} + Final processing in Golgi apparatus (trypsin-like enzyme cleaves off six amino acid “pro” segment — functional parathyroid hormone {single chain 84 amino acid polypeptide) — packaged into secretory vesicles -» eventual release) POSTERIOR THYROID GLAND ) PARATHYROID GLANDS Figure 35.3 Location of the parathyroid glands which produce parathyroid hormone. CA® CHANGES + Ca’ level changes detected by parathyroid cell surface receptor (calcium-sensing receptor) + Calcium-sensing receptor is G-protein meciated receptor + 1.C3* level -» hormone release inhibition + Large Ca#* amounts bind to receptor —» phospholipase C activation —» activated enzyme spits inositol bisphosphate (PIP,) diacylglycerol (026), inositol triphosphate (P.) +IP, affuses through cytoplasm to endoplasmic reticulum + binds to Ins3PR receptor on ligand-gated Ca channel —+ channel opens —+ calcium stored in endoplasmic reticulum released into cytoplasm — f intracellular calcium — stops binding of PTH-hoiding granules to chief cell membrane —+ no PTH release + | extracellular Co levels + PTH release fecitaton + Littlefno calcium-sensing G-protein receptor activation -+ no inhibition of PTH granule binging —» PTH release PTH SECRETION Stimuli + | serum Ca* concentration * Mild in serum magnesium (Mg) concentration * Tin serum phosphate — calcium phosphate complex formation — calcium receptor stimulation | + Adrenaline + Histamine Inhibitors +f serum Ca concentration + Severe | serum Mg concentration * CaleitriolChapter 35 Endocrine Physiology: Calcium & Phosphate Hormonal Regulation HIGH BLOOD CALCIUM LEVELS Fic ‘LOW BLOOD CALCIUM LEVELS Gon ssess jure 35.4 High calcium levels in blood inhibit PTH release from parathyroid cells, while low calcium levels in blood facilitate PTH release from parathyroid cells Magnesium + Involved in stimulus-secretion coupling + Moderate | serum Mg’ concentration promotes action of PTH on renal mineral resorption + Severe hypomagnesemia (eg. alcoholism) inhibits PTH secretion, causes PTH resistance EXTRACELLULAR CALCIUM INCREASE. + PTH — f extracellular calcium levels (three target organ systems) Bones + PTH receptors on osteoblasts + PTH binding — f cytokine release «© Receptor activator of nuclear factor KB ind (RANKL) + Macrophage colony-stimulating factor (M-CSF) + Inhibits osteoprotegerin (OPG) secretion (inhibition absence + free OPG binds to RANKL (decoy receptor) —» prevents RANK-RANKL interaction + PTH-induced cytokine release permits, RANK-RANKL interaction + multiple ‘macrophage precursors fuse —> ‘osteoclast formation (bone breakdown) + Bone breakdown — release of calcium, phosphate into blood (nitialy forms physioiogically-inactive compound) kidneys + PTH binds to receptors on cells of proximal convoluted tubules -» inhibits ‘sodium-phosphate co-transporters on. apical surface + | sodium, phosphate reabsorption —+ [urinary phosphate excretion + PTH binds to receptors on principal cells of distal convoluted tubules + sodiury calcium channel upregulation —+ {calcium reabsorption from urine Intestines + PTH promotes vitamin Da (cholecalcifero) conversion + active form + Cholecaleiferol synthesized by keratinocytes in skin epidermis when exposed to UV light [also found in foods) —+ cholecalciferoltrave's to liver enzyme 25-hydroxylase catalyzes conversion to 25-hydroxychalecalciferol {calcidiol) » 25-hydroxycholecalciferol travels to kidney’ proximal tubular cells + enzyme 1-aipha-hydroxylase (upregulated by PTH) converts it to OSMOSIS.ORG 2871.25-dihydroxycholecaleiferol (calcitriol. AKA active vitamin D = Active vitamin D travels to gastrointestinal (Gi) tract — enterocytes cof small intestine + upregulates calcium channels -+ | dietary calcium absorption OsTEOBLAST ‘BONE 4 CSF OSTEOCLAST RANKL FORMATION Noe INTERACTION —_>, nacRopHAGe te Figure 35.5 One way PTH increases extracellular calcium levels is by stimulating osteoclast formation in bone. chwaiéo PARATHYROID HORMONE. —conacvieo ‘TLE BINDS to: ‘THLE ‘* TUBULAR CELLS: ® PRINCIPAL CELLS: LS (4 J\ U-STOPS them REABSORBING “TupuLaR celts Hake na ne ‘Ne / Ga? CHANNELS PHOSPHATURIA t Ca" REABSORPTION Bram URINE Figure 36.6 The second way PTH increases extracellular calcium levels is by t urinary phosphate excretion and calcium reabsorption from urine, 288 OSMOSISORGChapter 35 Endocrine Physiology: Calcium & Phosphate Hormonal Regulation CHOLECALCIFEROL (0,) —> VITAMIN D (row) J! 1 r\\ Trae \ @ CALCIDIOL t mona. a (ACTIVE ViTAMun D ) 1 Ga" ABSORPTION ~~ won fram FOOD » ta. won eNTeRoc¥TES Figure 35.7 The third way PTH increases extracellular calcium levels is by helping convert cholecalciferol into vitamin D. It does so by upregulating enzyme 1a-hydroxylase, VITAMIN D osms.it/vitami + Steroid hormone (derived from cholesterol, fat soluble) — gene transcription stimulation = Promotes new bone mineralization © [serum Ca*, phosphate concentration = f available substrate concentration for bone mineralization VITAMIN D SOURCES Intestine + Absorbs precursors (biologically inactive) « Vitamin D,(ergocakciferal is derived from dietary plant sources + Vitamin D, (cholecalciferl) is derived from dietary animal sources ‘Skin + Skin keratinocyte exposure (stratum basale, stratum spinosum) to UV light + vitamin D, production + 7-dehydrocholesterol reacts with UVB light (wavelengths between 270- 300nm) — vitamin D, PRECURSOR ACTIVATION + Ergocaleiferol, cholecaciferol reach small intestine lumen — packaged in small fat- soluble sacs (micelles) with ad of bile salts diffuse through apical membrane of absorptive intestinal cells enterocytes) + Within enterocytes inactive vitamin D precursors integrate into lipoproteins (chylomicrons) —+ exit into lymphatic system —+ drain into blood circulation (hepatic portal vein) + bind to carrier proteins (vitamin D-binding protein! albumin) + transported to iver + Hepatocytes contain 25-hydroxylase — hydroxy! group added to carbon 25 (C25) of ergocaleifero, cholecalciferol —+ 25-hydroxycholecaleiferol (calcifediol) cakifediol (primary vitamin D circulating form) reenters blood bound to carrier proteins: * Hepatic hydroxylation requires NADPH, 0,,, Mg* (not cytochrome P-450) + Blood transports calcfediol to renal proximal tubules — proximal tubule cell mitochondria contain 1a-hydroxylase + hydroxyl added to C1 + 1,25 cihydroxycholecaliferol (calcitriol active vitamin D form) OSMOSIS.ORG 289H_PLDS PACKAGED wth é BILE SALTS into MICELLES ENTEROCYTES ey SHALL INTESTINE Ly B00 weparocyTes ue KiDNews Figure 38.8 Conversion of vitamins D, and D, into active vitamin D. 290 OSMOSISORGChapter 35 Endocrine Physiology: Calcium & Phosphate Hormonal Regulation Alternative pathway + Hydroxylation at C24 —+ biologically inactive 24,25-dinydroxycholecalcierol + Pathway choice regulated by blood calcium level, parathyroid hormone + C1 hydroxylation occurs as response to | calciumiphosphate levels += la-hydroxyiase activity t through | plasma Ca* concentration, t circulating PTH levels, | plasma phosphate concentration’ = C1 phosphorylation requires NADPH, 0,,Mg", cytochrome P-450 pathway + if calcium levels sufficient, inactive metabolite preferentially produced ‘VITAMIN D ACTIONS Bone + Acts synergistically with PTH -» osteoclast activity stimulation — bone resorption old bone demineralization —> t Ca”, phosphate concentration for new bene mineralization osTeoBLAsT Kidney + Stimulates Ca*, phosphate reabsorption Intestine + Increases Ca, phosphate absorption + Induces vitamin D-dependent Ca’ binding protein synthesis (calbindin D-28K) * Systolic protein + binds four Ca! + Intestinal Ca® absorption mechanism + Ca* diffusion: intestinal lumen —> cell (through electrochemical gradient) + Inside cel calbindin D-28K binds Ca®* —+ Ca” pumped across basolateral membrane by Ca®-ATPase BONE RANKL FORMATION: Nome INTERACTION —__, ac RopHAGE so Figure 35.9 Vitamin D stimulates osteoctast formation, increasing blood calcium and phosphate concentrations. OSMOSIS.ORG 291.rroxnaL, ACTIVE VITAMIN D conaréo ‘STIMULATES * TUBULAR CELLS: eo ‘Ne’ / PO, COTRANSPORTERS \ CALBINDIN D-28K SYNTHESIS ‘SYNTHESIS 4 . t PO, REABSORPTION 1 Ga? REABSORPTION Figure 35410 Vitamin D stimulates calcium and phosphate reabsorption in kidneys. ACTIVE VITAMIN D ‘STIMULATES. 1 cALBIDOD.2B% SINTHESS 1 Ne 1 COTRANSFORTERS Ne /P0> irens ENTEROCYTES, Figure 3544 Vitamin D stimulates calcium and phosphate absorption in the small intestine by increasing synthesis of calbindin D-28K and sodiumfphosphate cotransporters, 292 OSMOSISORGNOTES 276 OSMOSISORG Lt Lo) Tat SVB fe) Ui fel Saas) SYNTHESIS OF ADRENOCORTICAL HORMONES osms.it/adrenocortical-hormone-synthesis + Synthesized from cholesterol: carbon + Different enzymes found in different layers skeleton, 21-carbon molecules; circulation _—_ according to which hormones synthesized supplies cholesterol which enters adrenal + Cholesterol desmolase found in all layers land cells via endocytosis + Rate-limiting step: stimulated by = Some synthesized de novo > both 2drenocortcotrpic hormone (ACTH) forms stored in cytoplasmic vesicles converts cholesterol to pregnolone + Cytochrome p450 using O,,adrenodoxin _« Corticosteroid is common name for reductase, adrenodoxin transfers H from steroid hormones made in cortex inclde NADPH producing energy using reduction _rineralocotioids, glucocorticoids reactions coocesTeRoL ‘CHOLESTEROL DESMOLASE J trutie Ese NOLONE Zain = ALDosTEtoNe cohen ay cra Zon | > conmisa. FRSCiCULATR Zo nee Mays? TESTOSTERINE LesTROGEN Figure 3341 Three zones of adrenal cortex secrete steroid hormanes under control of ACTH, which is released by anterior pituitary. Adrenal cortex cells first convert cholesterol to prognenolone using enzyme cholesterol desmolase. Prognenolone is then converted into aldosterone in zona glomeruiosa, cortisol in zona fasciculata, and testosterone and estrogen in zona reticularis,Chapter 33 Endocrine Physiology: Adrenal Hormones Mineralocorticoids + Synthesized in zona glomerulosa + Synthesized in zona reticularis, + Example: aldosterone + Examples: dehycroepiancrosterone + Aldosterone synthase required and (DHEA), androstenedione found only in zona glomerulosa, converts _* 17.20-Wyase responsible for conversion of cortisone + aldosterone 21B- and swanky e178 L1B-hydroxylase a PP BB. PREGNENOLONE —> PROGESTERONE ——> 11. D0C ——> CORTICOSTERONE ? 3p-¥ " p- gosta p 2L-HYOROAYASE 11 -WOROKHLASE HoLesTeROL ALDOSTERONE. ‘aLpostenoNe ‘SUNTHASE of eee Figure 33.2 Aldosterone synthesis in zona glomerulosa. Aldosterone synthase is stimulated by hormone angiotensin Il which is produced in lungs in response to low blood pressure, volume, ConTisoL PREGNENOLONE ———> 1704 oe $T04-WYORGXVLASE io ai of? — PROGESTERONE ————— 1704- (OH) PROGESTERONE —> 11-DEOKYCORTISOL. 1T0L- WYOREXYLASE 21- HYDRORNLASE. a ae Figure 33.3 Cortisol synthesis in zona fasciculata OSMOSIS.ORG 277278 OSMOSISORG (Gare) -> anonocens i fa 17 &- (OH) PREGNENOLONE ——> Dek ——————> NDROSTENEDIOL, 1. 20-nse 3p-¥50 1p 45 5p-4s0 1704 () PROGESTERONE ————> ANDROSTENEDIONE ———> TESTOSTERONE 1.20. wise ai a inp -1s enmomse 17B- ESTRADIOL sr ESTROGEN Figure 33.4 Androgen synthesis in zona reticularis. CORTISOL + Steroid glucocorticoid hormone secreted by adrenal cortex: has metabolic, anti- inflammatory, immunosuppressve, vascular effects + Normal pulsatile secretion, approximately 10 surges in diumal (daly) pattern + Concentration highest in morning, lowest in evening Diurnal pattern: maintained by hypothalamic suprachiasmatic nucleus; acts as central pacemaker for hhypothslamic-pitutary-adrenal (HPA) axis; adrenals maintain diural pattern of sensitivity to ACTH Secretion regulation + Stress (infection, trauma, initiation of “ight or flight’ response, psychological stressors), 1 sympathetic activity, physical activity, | blood glucose —» hypothalamus simulated to release coricotropin-eleasing hormone (CRH) — anterior pituitary releases adrenocorticotropic hormone (ACTH) > adrenal medulla secretes glucocorticoids (ovimariy cortisol) — target tissues + Negative feedback of cortisol to hypothalamic-ptuitary axis {cortisol Major effects * Metabolic: blood glucose (considered diabetogenic hormone} by 1 hepatic, alycogenoiysis. 1 lipolysis. | protein catabolism, | cellular insulin sensitivity, 1 appetite + Immune: | intensity of immune, inflammatory responses by | production of arachidonic acid metabolites (eg. prostaglandin, thromboxane, leukotrienes} L production of interleukins, interferon, ‘tumor necrosis factor; | T cell proliferation: { neutrophil phagocytosis + Vascular: involved in normal vascular bload pressure maintenance: supports vascular smooth muscle responsiveness to catecholamine vasoconstrctve effects + Other: | connective tissue froblast proliferation, | bone formation, t renal blood flow, t erythropoietin release, alters sleep patternsChapter 33 Endocrine Physiology: Adrenal Hormones HYPOTHALAMUS * CORTICOTROPIN RELEASING onwone v ANTERIOR, PITUITARY ‘ apnenoconricarronic —> ADRENAL. onnone (cr) “GLAND INNER MEDULLA Figure 33.8 Cortisol secretion regulation. OSMOSIS.ORG 279NOTES 280 OSMOSISORG NOTES BAT NAA Ulla) GLUCAGON + Peptide hormone secreted by pancreatic alpha cells + Important for blood glucose regulation, ‘long with insulin + Synthesis * Preproglucagon ~» proglucagon —» ‘glucagon Secretion regulated mainly by glucose * | glucose levels between meals or while sleeping —> | insulin — glucagon secretion stimulation — hepatic glycogenolysis, gluconeogenesis + blood glucase levels Other factors that regulate glucagon secretion * Sympathetic nervous system + Adrenaline (a, receptors) + Parasympathetic nervous system = Acetylcholine M, receptors) + Alanine, arginine E49, from high protein meal + Cholecystokinin, somatostatin + Exercise GLUCAGON SIGNALING PATHWAY + Glucagon receptoris a heterotrimer + G-protein coupled receptor that contains ©, B,y subunits * Glucagon binds to receptor ~» activates G, protein + a subunit released —+ activates adenylate cyclase 1 cAMP — activates protein kinase A + phosphorylation cascade —+ transcription factor activation > effects TARGET CELL MEMBRANE Figure 3441 Glucagon exerts its effects by binding to G-protein coupled receptors on the membranes of liver and agipose cells. EFFECTS OF GLUCAGON + Primary action is to increase blood glucose when it falls below normal range + Carbohydrates: 1 blood glucose levels » Stimulates alycogenolysis in liver, muscle » Stimulates gluconeogenesis in ver, kidney + Inhibits hepatic glycolysis + Fats: | fatty acids, keto acid levels in blood + Inhibits fatty acid synthesis, oxidation in liver + Inhibits fat deposition in adipose tissue * Stimulates lipolysis » Stimulates keto acid productionChapter 34 Endocrine Physiology: Pancreatic Hormones GLUCAGON DURING FASTING: secretes ( = vncgnins det Bee, ALPHA cell t GLUCOSE LEVELS STOMACH PANCREAS BReagnown = scrcaton a Figure 34.2 Glucagon is secreted by pancreatic alpha cells when glucose levels are low. It increases glucose levels in the bloodstream by inducing the breakdown of storage molecules in the liver and adipose calls SMALL INTESTINE INSULIN Coe AUTU + Peptide hormone secreted by pancreatic beta cells + Important for blood glucose regulation * Consists of A and B amino acid chains connected with two disulfide (-S-S-] bonds SYNTHESIS * Preproinsulin —» proinsulin — insulin + During insulin synthesis, protein called C-peptide cleaved off, secreted together with insufin in equimolar amounts within secretory vesicles —» C-peptide used to ‘measure insulin levels, SECRETION Secretion regulated mainly by glucose + Carbohydrates consumption —> { glucose = passive diffusion into beta cells through GLUT2 transporters —+ stimulation of insulin secretion Other factors that stimulate insulin secre- tion + 1 fatty acid, amino acid levels in blood + Parasympathetic nervous system » Acetylcholine M, receptors) + Sympathetic nervous system * Adrenaline (B, receptors) + Growth hormone (GH), adrenal cortcotropic hormone (ACTH) OSMOSIS.ORG 281PREPROINSULIN sicnat verre @ w-cHan A- CHAIN — Figure 34.3 Insulin synthesis. PHASES OF INSULIN RELEASE + Two phases First phase + Involves L-type Ca” channels + Rapialy triggered release of preformed secretory vesicles + Lasts 10 minutes Second phase + Involves R-type Ca®* channels + Slow release of newly formed secretory vesicles + Lasts 2-3 hours INSULIN SIGNALING PATHWAY 282 OSMOSISORG + Insulin receptor is a tetramer += Contains two extracellular a subunits connected by disulfide bonds. two intracellular B suburits connected to each a subunit + Insulin binds to a subunits — activates tyrosine kinase activity in B subunits —» B subunit autophosphorylation > insulin receptor substrates [IRS] phosphorylation cascade -+ transcription factor activation —> effects EFFECTS OF INSULIN + The primary action of insulin is lowering blood glucose levels when above normal range + Carbohydrates: | blood glucose levels » Translocates GLUT4 transporters to muscle, adipose cell membranes —> facltates call uptake of glucose + Activates alycogen synthesis in iver, muscles + Inhibits hepatic iycogenoysis, gluconeogenesis + Fats: | fatty acid, keto acid levels in blood * Inhibits faty acids mobilization, oxidation » Stimulates fat deposition in adipose tissue + Inhibits lipolysis * Inhibits keto acid formation in liver + Proteins: anabolic effect + Stimulates amino acid, protein uptake ® Stimulates protein synthesis * Inhibits proteolysis + Other: | K*levels in blood + Increases potassium uptake » Stimulation of cell growth, gene expression ‘TARGET CELL. MEMBRANE SIGNAL: INSULIN RECEPTOR 2 ALPHA SUBUNITS, By suas os Figure 34.4 Insulin exerts ts effects by binding to alpha subunits of insulin receptor, ‘which leads to signal transduction within cellChapter 34 Endocrine Physiology: Pancreatic Hormones INSULIN AFTER « NEAL: SECRETES. SSB & | GLUCOSE LEVELS ‘by PROMOTING CONVERSION of STOMACH ~ ‘SMALL ENERGY MOLECULES: PANCREAS ‘ LARGE STORAGE MOLECULES if a= ese ance moins 1 anne Diem Rem Figure 34.5 Insulin is secreted by pancreatic beta cells when glucose levels are high. it promotes conversion of glucose ~+ glycogen in lver, fatty acids — fat, and amino acids — protein. SOMATOSTATIN + Peptide hormone secreted by pancreatic EFFECTS OF SOMATOSTATIN deta cells + Inhibits secretion of insulin, glucagon * Inhibits pancreatic exocrine secretion Factors that regulate somatostatin secre- tion + Inhibits secretion ofall gastrointestinal hormones (gastrin, cholecystokinin, + Ingestion of glucose, fatty aids, amino baron oases ty secretin, moiin etc} * Glucagon + Decreases gastrantestinal moti, blood + Sympathetic nervous system flow, gastric emptying + Beadrenergic agonists SOMATOSTATIN SIGNALING PATHWAY + Somatostatin receptor is @ G-protein coupled receptor + Somatostatin binds to receptor —+ activates G protein — inhibits adenylate cyclase —+ | CAMP — | Ca? inhibitory effect OSMOSIS.ORG 283