Module 7 Flashcards
Adrenal Medulla: Embryology
- Neural crest → neuroblasts → autonomic postganglionic neurons, adrenal medulla, spinal ganglia
- Consists of chromaffin cells (pheochromocytes) = neuroectodermal derivatives and functional analogues of postganglionic fibers (ANS)
- Early fetal life: secretes norepinephrine (NE)
Morphology
- Grossly, reddish-brown
- Enlarged, specialized sympathetic ganglion
- Neuroendocrine transducer (neural signal stimulates hormonal secretion)
- The ONLY autonomic neuroeffector organ w/o a 2-neuron motor innervation
- Innervated by long sympathetic preganglionic, cholinergic neurons forming synaptic connections with chromaffin cells
- Small clumps of chromaffin cells found extra-adrenally and retroperitoneal(aortic and sympathetic ganglia
Adrenal Medulla
Adrenal Medulla: Histology
- 2 adrenomedullary chromaffin cells: 1) NE-secreting 2) Epinephrine (Epi)- secreting
- The hormones are stored in chromaffin granules (osmiophilic, electron-dense, membrane-bound secretory vesicles)
- 80-90% of chromaffin granules synthesize Epi and 10-20% secrete NE
Adrenal Medulla: Histology 2
- Contains dopamine, proteins, lipid, ATP
- Has dopamine β hydroxylase
- Has soluble acidic proteins called chromagranins
- Chromaffin granules are exocytosed in fenestrated capillaries
Adrenal Medulla: Innervation
- Preganglionic sympathetic fibers through the splanchnic nerve
- Myelinated(type B) secretomotor fibers coming from lower thoracic segments (T5 and T9) of the ipsilateral intermediolateral gray column of the spinal cord
- Chromaffin cells are functional analogues of postganglionic fibers; DO NOT HAVE AXONS
Adrenal Medulla: Vascular Supply
- Branches of renal and phrenic arteries reach the outer capsule
- 2 ways the adrenal gland is perfused: 1) portal circulation 2) direct arterial supply via medullary artery traversing the adrenal cortex
- Blood from the capillary plexus on outer adrenal capsule drain into venous sinuses and supply the adrenal medulla
- Single central adrenal vein along the longitudinal axis of the gland
Effector organ: Most vascular smooth muscle, pupils
Relative Affinities: NE>Epi
Signal Transduction Mechanism: activates IP3
Effect on effector organ: Excitatory
Alpha 1
Effector organ: CNS, Platelets, adrenergic nerve terminals (autoreceptors), some vascular smooth muscle, adipose tissue
Relative Affinities: NE>Epi
Signal Transduction Mechanism: inhibits CAMP
Effect on effector organ: Excitatory
Alpha 2
Effector organ: CNS, cardiac muscle, kidney
Relative Affinities: NE = Epi
Signal Transduction Mechanism: activates cAMP
Effect on effector organ: Excitatory
Beta 1
Effector organ: Some blood vessels, respiratory tract, uterus
Relative Affinities: Epi»NE
Signal Transduction Mechanism: activates cAMP
Effect on effector organ: Inhibitory
Beta 2
Effector organ: Adipose tissue
Relative Affinities: NE=Epi
Signal Transduction Mechanism: activates cAMP
Effect on effector organ: Excitatory
Beta 3
Epidemiology: Adults; both sexes; all ages, especially 30-50 years
Biologic behavior: 90% benign, 10% malignant
Secretion: High levels of catecholamines, most secrete norepinephrine
Clinical presentation: Sustained or episodic hypertension, sweating, palpitations, hyperglycemia, glycosuria
- Occasionally asymptomatic (found incidentally on CT scan or MRI)
Macroscopic features: Mass, often hemorrhagic, 10% bilateral, 9-23% extra adrenal
Microscopic features: Nests of large cells, vascular stroma
Pheochromocytoma
Three amines that are synthesized from tyrosine in the chromaffin cells of the adrenal medulla.
dopamine, norepinephrine, and epinephrine
The major product of the adrenal medulla is __.
epinephrine
The conversion of tyrosine to epinephrine requires four
sequential steps:
(1) ring hydroxylation;
(2) decarboxylation;
(3) side-chain hydroxylation to form norepinephrine; and
(4) N-methylation to form epinephrine.
__ is the immediate precursor of catecholamines
Tyrosine
- is the rate-limiting enzyme in catecholamine biosynthesis
- is found in both soluble and particle-bound forms only in tissues that synthesize catecholamines
- it functions as an oxidoreductase, with tetrahydropteridine as a cofactor, to convert l-tyrosine to
l-dihydroxyphenylalanine (l-dopa).
tyrosine hydroxylase
- is a monooxygenase and uses ascorbate as an electron
donor, copper at the active site, and fumarate as modulator. - is in the particulate fraction of the medullary cells, probably in the secretion granule; thus, the conversion of dopamine to norepinephrine occurs in this organelle.
Dopamine a-Hydroxylase (DBH)
- catalyzes the N-methylation of norepinephrine to form epinephrine in the epinephrine-forming cells of the adrenal medulla.
- Since __ is soluble, it is assumed that norepinephrine-
to-epinephrine conversion occurs in the cytoplasm. - synthesis is induced by glucocorticoid hormones that reach the medulla via the intra-adrenal portal system.
Phenylethanolamine-N-Methyltransferase (PNMT)
(Anatomy)
- Firm, reddish brown, smooth
- 2 lateral lobes and connecting central isthmus
- 30-40 g
- Adherent fibrous capsule
- Highly vascular: one of the highest blood flow rates per gram tissue
Thyroid Gland
Thyroid Gland: Histology
- Follicle (acinus) = functional unit surrounded by a rich capillary plexus
- Single, cuboidal epithelium
- TSH has an effect on the cell height of the follicular cells
- Columnar: active; - flat: inactive
- Follicles depleted of colloid when stimulated
- Lumen contains colloid: clear amber, proteinaceous fluid
- Microvilli extending into the colloid from the lumen
- Parafollicular cells ( C cells): secrete calcitonin
Thyroid Gland: Thyroid hormones
- Iodothyronines
- Phenol derivative
- Thyroxine (T4) and T3: biologically active
- Molar activity (T3 /T4) 10: 1
- Secretory ratio (T4 /T3) 10-20:1
- Plasma concentration ratio ( free T4 /T3) 2:1
- Storage ratio to thyroglobulin ( T4 /T3) 10:1
- rT3 : biologically inactive formed by peripheral conversion by 5-deiodinas
Thyrocytes
- 3 functions: 1) synthesize thyroglobulin 2) collect and transport iodine to colloid 3) release thyroid hormones from the thyroglobulin
- Rests on a basal lamina
- Microvilli found adluminal (near apical area)
Thyroid Gland
- Thyroglobulin: 660,000 Da glycoprotein
- Site of T4 and T3 synthesis and storage
- Each contains 134-140 tyrosyl residues
- 25-30 are iodinated
- 6-8 form iodothyronines
Thyroid Gland
- is the precursor of T4 and T3
- is a large iodinated, glycosylated protein with a molecular mass of 660 kDa.
- is composed of two large subunits.
- contains 115 tyrosine residues, each of which is a potential site of iodination.
- About 70% of the iodide in __ exists in the inactive precursors, monoiodotyrosine (MIT) and diiodotyrosine (DIT), while 30% is in the iodothyronyl residues, T4 and T3.
Thyroglobulin
When iodine supplies are sufficient, the T4:T3 ratio is about __
7:1
- a large molecule of about 5000 amino acids, provides the conformation required for tyrosyl coupling and iodide organification necessary in the formation of the diaminoacid thyroid hormones.
- It is synthesized in the basal portion of the cell and moves to the lumen, where it is a storage form of T3 and T4 in the colloid; several weeks’ supply of these hormones exist in the normal thyroid.
Thyroglobulin
Iodine intake
- In the US, 300-1000 micrograms of daily dietary iodine (averaging 500 ug/d)
- 150 micrograms: recommended minimum intake (≈ 1 mg/week) = euthyroidism
- Salt and bread
- Pregnant pts: 200 ug/d
- Goiter prevention: 75 ug/d
- Neonates: 40 ug/d
Thyroid Iodide
- 5-7 mg iodide in thyroid gland
- Sufficient for 2-3 months if no thyroidal secretion
- 95% in colloid as thyroglobulin
- 2/3 as inactive iodotyrosines
- 1/3 iodothyronines
- 5% found intracellularly in thyrocytes
- Largest iodide storage pool: thyroid gland
Thyroid Hormone Biosynthesis
1) Iodide Uptake
2) Iodide Oxidation
3) Iodide Organification
4) Coupling or Condensation
- Occurs at basal membrane
- Na+I- symporter and Na+ K- ATPase pump (secondary active transport; TSH-driven)
- 120-150 ug/d of Iodide is uptaken
- Lumen to cell iodide ratio 5:1
- Pendrin (I- Cl- transporter at apex)
- Radioactive iodide = useful therapeutic index for functional status of thyroid gland (10-35% daily uptake)
Iodide-131 and iodide -123 - Technetium -99 m
- Iodide Uptake
- mediated by thyroid peroxidase (TPO)
- Iodinium (I+) , iodate ion (IO3-), I, hypoiodous acid (HOI)
- Requires an oxidant (electron acceptor), H2O2
- Iodide Oxidation
- Iodination of tyrosyl residues in the thyroglobulin
- Occurs in exocytotic vesicles fused with the apical membrane
- Need TPO
- The substrate is the thyroglobulin
- Around 15 of 134-140 tyrosyl residues are iodinated
- First at position 3 of ring then position 5
- Iodide Organification
- T3 and T4 are formed w/in exocytotic vesicles near the apical border
- Held in peptide linkage with thyroglobulin
- T needs 2 DIT; T needs 1 MIT and 1 DIT
- TPO mediates this reaction
- Average distribution of iodothyronines: MIT – 23%, DIT – 33%, T4 – 35%, T3 – 7%, rT3 – 2%
- Coupling/Condensation
Thyroid Secretion
- Thyroid secretes 80 ug (103 nmol) of T4 and 4 ug (7 nmol) of T3 per day
- Folds of the apical cell membrane (lamellipodia) encircle bits of colloid bring them intracellularly via endocytosis
TSH-driven
Thyroid Secretion
- Endosomes fuse with lysosomes where peptide bonds are broken – releasing thyroid hormones, DIT, MIT in the cytosol
- Free T4 and T3 cross basal cell membrane and enter adjacent capillaries
- MIT and DIT are degraded into iodine and tyrosine via iodotyrosine dehalogenase/deiodinase
Recycled back into the colloid
Thyroid Hormone Transport and Metabolism: Normal Plasma Level
Normal plasma level T4 : 8 ug/dl (103 nmol/L) range 5 – 12 ug/dl or 65-156 nmol/L
Normal plasma level T3 : 0.15 ug/dl (2.3 nmol/L) range 0.08 – 0.22 ug/dl or 1.2-3.3 nmol/L
Thyroid Hormone Transport and Metabolism 1
Both are bound to plasma proteins such as albumin, transthyretin (aka thyroxine-binding prealbumin (TBPA) and thyroxine-binding globulin (TBG)
- 95% T4 is bound to plasma protein; 0.05% is free
- 5% T3 is bound; 0.5% is free
free portion is biologically active
Thyroid Hormone Transport and Metabolism: TBG and Half Life
TBG binds70-75% of T4; Transthyretin 15-20%; albumin 9-10%
TBG binds 70-75% of T3; transthyretin 0%; albumin 25-30%
T4 half-life is 6-7 days; T3 is 30 hrs
T3 acts more rapid and has a shorter half-life; 3-5 times potent on a molar basis
Thyroid Hormone Transport and Metabolism 2
Metabolized in liver, kidneys by deiodination and glucuronidation
33% of T4 is converted into T3 via 5’ – deiodination
45% of T4 is converted into rT3 via 5 - deiodination
87% of T3 comes from peripheral conversion while 13% from thyroid secretion
After glucuronidation, both thyroid hormones are excreted into bile and reabsorbed enterohepatically
Regulation of Thyroid Secretion 1
- Stimulated via TSH or thyrotropin
- TSH is stimulated by thyrotropin-releasing hormone (tripeptide) which comes from the hypothalamus and which alters TSH’s glycosylation
- 2 – subunit glycoprotein around 211 amino acids
- α-subunit (chromosome 6) is identical to FSH, LH, placental hCG
- β-subunit (chromosome 1) confers specific binding and biologic activities
Regulation of Thyroid Secretion 2
- Half-life: 60 mins
- Ave. plasma levels: 2 mU/L (range 0.4-4.8 mU/L)
- Upper limit of 2.5 – 3.0 mU/L if pt has no autoantibodies, no goiter, no family hx of thyroid disease
- Debate on age-specificity: 7.5 mU/L in pts80 yrs old
- Circadian pattern: rising in the afternoon and evening, peaking after midnight then decline afterwards
Regulation of Thyroid Secretion 3
- Free T4 and T3 inhibit TSH secretion both directly and indirectly by TRH biosynthesis in hypothalamus
- TSH inhibited by stress via glucocorticoid inhibition of TRH
- In infants but not in adults, TSH secretion is increased by cold and inhibited by warmth
- Dopamine and somatostatin inhibit TSH secretion
Thyroid Hormone
- Thyroid hormones increase Na-K ATPase activity, increase heat production, stimulate oxygen consumption, tissue growth and maturation, lipid metabolism, increase cardiac contractility, increase intestinal carbohydrate absorption
- Thyroid hormones and catecholamines epi and NE have interrelated effects
- Increase metabolic rate and stimulate nervous system and heart
- transcriptional genomics: increased numbers of β-adrenergic receptors in heart, skeletal muscle, adipose tissue and lymphocytes
Condition: \_\_ Concentrations of Binding Proteins: Normal Total Plasma (T4,T3,RT): High Free Plasma (T4,T3,RT): High Plasma TSH: Low
Primary Hyperthyroidism
Condition: \_\_ Concentrations of Binding Proteins: Normal Total Plasma (T4,T3,RT): Low Free Plasma (T4,T3,RT): Low Plasma TSH: High
Primary Hypothyroidism
Condition: \_\_ Concentrations of Binding Proteins: High Total Plasma (T4,T3,RT): High Free Plasma (T4,T3,RT): Normal Plasma TSH: Normal
Drugs (estrogen, methadone, heroin, perphenazine, clofibrate), pregnancy, acute and chronic hepatitis, acute intermittent porphyria, estrogen-producing tumors, idiopathic, hereditary
Condition: \_\_ Concentrations of Binding Proteins: Low Total Plasma (T4,T3,RT): Low Free Plasma (T4,T3,RT): Normal Plasma TSH: Normal
Drugs (glucocorticoids, androgens, danazol, asparginase), acromegaly, nephrotic syndrome, hypoprotenemia, cirrhosis, testosterone-producing tumors, hereditary
(Anatomy)
- 4 gray-tan to yellow gray small rounded organs
- Each weighing 30-40 mg (120-160 mg)
- Superior pair arise from 4th branchial pouches
- Superior pair maybe attached to thyroid capsule posteriorly or rarely embedded
- Blood supply: inferior thyroid artery superior thyroid artery
Parathyroid Gland
(Anatomy)
- Inferior pair from 3rd branchial pouches similar to thymus
- Inferior thyroid artery
- Can ectopic found in thymus or anterior mediastinum, carotid sheath, pericardium, pharyngeal submucosa
- 10% of people have supernumerary __
Parathyroid Gland
Parathyroid Gland: Histology
- Composed of 1) Chief cells 2) clear cells and 3) oxyphil cells
- Chief cells: small in diameter (4-8 um) with central nuclei, parathyroid hormone (PTH) synthesis
- In active state: prominent ER and dense Golgi bodies
- Clear cells: chief cells with more glycogen
- Oxyphil cells: appear after puberty, larger than chief cells (6-10um); number increases with age
- Not clear if they secrete PTH and if they are derived from chief cells
- Parathyroid gland contains fat which increases with age (60-70% in elderly)
Parathyroid Gland: Physiology
- 99% of total body Ca is in skeleton and teeth
- Remainder in ECF: ionized, protein-bound and complexed
47% of total blood Ca is protein-bound to albumin and globulin; 47% ionized; 6% is complexed to organic ions such as citrate, phosphate and bicarbonate - Serum ionized calcium control vital cellular functions: hormone secretion and action, muscle contraction, neuromuscular transmission, blood clotting
Parathyroid Gland: Physiology 2
- Calcium binding to albumin is pH dependent: increasing with alkalosis, decreasing with acidosis hence if there is hypocalcemia, acidosis tends to be protective
- PTH secretion is inversely related by an inverse sigmoidal curve
- PTH secretion is highly attuned to very small calcium concentrations
Calcium, Phosphorus and Bone Metabolism
- Calcium-sensing receptor (CaSR) is expressed by parathyroid and other cell types (kidneys, thyroidal C cells, brain etc)
- Detect extracellular Ca concentration
- Activated by increases in calcium concentration
- Inhibits PTH secretion
- Inhibits parathyroid glandular hyperplasia
Calcium, Phosphorus and Bone Metabolism 2
- PTH: 115 amino acid (preproPTH) is successively cleaved within the cell to form the mature 84 aa peptide hormone which is packaged into secretory granules
- Very short half-life: 10 mins
- Metabolized in liver, other tissues to midregion
- Carboxyl terminal forms: probably inactive
- Accumulate to very high levels in renal failure pts: kidney excretion
2 types of PTH receptors:
1) type 1 (PTH and PTHrP)
2) type 2 (PTH specific)
PTH-1 vs PTH-2
PTH-1: activates adenylyl cyclase and produces cAMP
Coupled to phospholipase C : IP3 and DAG
PTH-2: found in brain, pancreas, testis, placenta
Natural ligand: tubuloinfundibular peptide (hypothalamic peptide)
Effects of Parathyroid Hormone
- When serum Ca concentration drops, PTH is rapidly released
- Ca reabsorption in distal tubule and medullary thick ascending limb of Loop of Henle
- Calcium release from bones
- Enhanced intestinal calcium absorption
- Chronic PTH surges increases renal 1,25-(OH)2 D3 production
- Calcium and phophate absorption in small intetine
- At least 24 hrs to restore normal calcium levels
- Any increase in vitamin D3 inhibits PTH synthesis
Effects of Parathyroid Hormone 2
- Inhibits Na-dependent phosphate transport in the proximal tubules
- Serum phosphate levels are thought to affect PTH
- Hypophosphatemia enhances 25-OH D3 conversion to 1,25 (OH)2 D 3in kidney
- Hyperphosphatemia inhibits 1, 25 – (0H)2 D3 production and lower serum calcium by complexing with it in the circulation
- Increases urinary excretion of bicarbonate through its action on the proximal tubule causing proximal renal tubular acidosis
Effects of Parathyroid Hormone 3
- In hyperparathyroidism, hypophosphatemia and hyperchloremic acidosis can be seen
- Dehydration common in moderate to severe hypercalcemia
- An effect of hypercalcemia on vasopressin action in the thick ascending limb
- High calcium interacting with renal CaSRs blunt the ability of endogenous vasopressin to stimulate water reabsoprtion hence vasopressin-resistant nephrogenic diabetes insipidus
Effects of Parathyroid Hormone 3
- PTH enhances bone resorption to restore normocalcemia
- Enhances osteoclastic activity through stimulation of RANK-L (receptor activator of nuclear factor kappa B ligand) which is expressed on cells with osteoblastic lineage (stromal cells and osteoblasts)
- RANK-L interacts with receptor RANK found on osteoclast lineage to stimulate differentiation and function (bone resorption)
- Once resorption ceases, bone formation ensues because resorption and formation are coupled
- In primary and secondary hyperparathyroidism , PTH production is excessive
- Net bone loss may occur over time
- 141 amino acid peptide homologous at its amino terminal region with PTH
- Recognized by PTH-1 receptor
- Increases bone resorption, increase phosphate excretion, and decreases renal calcium excretion through similar mechanisms with PTH
- Secreted by tumor cells and originally identified as the cause of hypercalcemia of malignancy that mimics hyperparathyroidism
- Produced by many tissues
- Functions as a tissue growth and differentiation factor at local level and a regulator of smooth muscle tone
Parathyroid hormone-related Peptide
Stimulates chondrocyte proliferation and inhibits cartilage mineralization
- Regulates normal development of skin, hair follicles, teeth, breast
- Plays an important role in determining calcium content of milk from lactating animals
- New studies reveal that PTH and PTHrP interact with the receptor causing different consequences
- Each peptide has different effects on the conformational state and the extent of activation of the receptor
- PTHrP can be transcribed from a promoter that bypasses the signal peptide and can enter the nucleus
Parathyroid hormone-related Peptide
- Prohormone produced in the dermis in response to UVB exposure
- Metabolized into its active form in the liver first then in the kidney
- The amount of sunlight exposure necessary to produce sufficient __ is difficult to estimate because of individual differences in skin pigmentation, latitude and time of day
Vitamin D
Dietary sources are relatively modest in vit D content
Fish ingest UV-irradiated sterols in phytoplankton and zooplankton that are converted into vit D and stored in their livers
7 – dehydrocholesterol stored in the epidermis is converted into vit D3 (cholecalciferol) by UV (280-310 nm)
- Breakage of the B ring of the cholesterol to form a secosteroid
- Hormones with an intact cholesterol ring are called steroids
- Similar thing occurs in plants but produces vit D2
- Vit D2 is produced in humans but does appear to have a decreased binding affinity for vitamin D binding protein resulting in enhanced clearance
- This is particularly evident when large intermittent doses are given rather than daily in vit D deficiency treatment
Vitamin D (1)
- Cutaneous synthesis is sufficient to prevent rickets although there is insufficient UVB radiation during winter months in the US hence in 2011, the Institute of Medicine revised the recommended intakes of 400 IU/d up to 1 year of age to 600 IU/d for 1-70 years and 800 IU/d for greater than 70
- Dietary supplements included vit D2 (ergocalciferol) and vit D3 (cholecalciferol)
- Milk in the US is supplemented with 400 IU of vit D per quart
- There is no toxicity with enhanced sun exposure since there is photo-conversion of excess vit D to inactive metabolites
- Vit D produced in skin is lipophilic and transported to liver bound to albumin and a specific vit D- binding protein (DBP)
Vitamin D (2)
- Ingested vit D is transported via chylomicrons to the liver
In the liver: vit D is hydroxylated to 25 – hydroxyvitamin D
*Not closely regulated
*25-(OH) D is transported via DBO in the serum to target tissue and stored in liver and adipose
*Clinical test for Vit D3 is measurement of 25-(OH) D3
Vitamin D (3)
- Final metabolic processing in renal cortex
- Converted to 1,25 – (OH)2 D3
- Increased by PTH, hypophosphatemia and hypocalcemia
- Decreased by hypercalcemia, hyperphosphatemia, fibroblast growth factor-23, decreased PTH
- Another control mechanism: 1,25 – (OH)2 D induces 24- hydroxylase which degrades vit D3
Vit D Mechanism
- Vit D receptor is a member of the steroid receptor superfamily of nuclear DNA-binding receptors
- Involves RNA and protein synthesis
- 1,25-(OH)2D has 1000-fold affinity than 25- (OH) D
- Primary target organs: intestine and bone
- Stimulate intestinal calcium transport in duodenum
Vit D Mechanism
- A paracellular route is also possible done passively
- Stimulate active phosphate transport but passive transport dominates this
- Vit D def leads to rickets ( defect in mineralization)
- Defect in mineralization results mainly from Ca and phosphate decreased supply
- 1,25 –(OH)2 D also stimulates osteoclasts to resorb bone to maintain extracellular calcium levels
- plays a central role in phosphate homeostasis, vit D metabolism, bone mineralization
- Produced by many tissues of body but primary source comes from osteocytes
- Phosphate levels rise (renal failure, high-phosphate diet) __ levels elevate
- Levels fall (phosphate depletion, low-phosphate diet), __ levels decrease
- It reduces expression of sodium phosphate co-transporters in kidney and intestine
- Leads to rapid phosphate excretion in kidneys and reduced intestinal phosphate absorption
Fibroblast Growth Factor-23
- Inhibits renal production of 1,25- (OH)2 D
- Direct actions mediated by FGF receptors and co-receptor transmembrane protein named KLOTHO
- __ diseases causing excessive production due to gain of function mutations include X-linked hypophophatemic rickets, autosomal dominant hypophosphatemic rickets, tumor-induced osteomalacia
- FGF mutations causing loss of function can cause syndromes of ectopic calcification, abnormal mineralization, hyperphosphatemia
Fibroblast Growth Factor-23
- Secreted by parafollicular or C cells in the thyroid gland (0.1% of total mass)
- C cells are neuroendocrine cells derived from ultimobranchial body
- Spindle shaped or polygonal cells
- Arranged in nests, cords, and sheets
- is a 32 amino acid peptide with 7 member amino terminal disulfide ring and carboxyl terminal prolineamide
- Differential processing of the calcitonin gene can give rise to calcitonin and other calcitonin gene-related peptides in neurons
- Hypercalcemia stimulated calcitonin release through CaSR
- GI hormones cholecystokinin and gastrin are __ secretagogues
Calcitonin
- interacts with kidney (cortical ascending loop of Henle) and bone receptors (osteoclasts)
- Stimulation of adenylyl cyclase and cAMP generation
- Main function: lower serum calcium
- Inhibits osteoclastic bone resorption
- Blocks Ca and Phosphate release
Calcitonin
- It has modest effects in kidney tom produce mild phosphaturia
- Overall importance of calcitonin in maintaining calcium homeostasis is unclear
- Serum calcium concentrations are normal in pts after total thyroidectomy
- In pts with medullary thyroid carcinoma, calcitonin rises to very high levels but has no effect on serum calcium levels causing an “escape”
Calcitonin
Gonads
- Bifunctional organs – produces germ cells and sex hormones
- Testes in males - Produce spermatozoa and testosterone
- Ovaries in females - Produce ova and estrogen and progesterone
SYNTHESIS OF TESTOSTERONE
- Takes place in the Leydig cells
- Immediate precursor is cholesterol
- Rate-limiting step is the delivery of cholesterol to the inner mitochondrial membrane by the transport protein Steroidogenic acute regulatory protein (StAR)
SYNTHESIS OF TESTOSTERONE: Pathways
- Progesterone (Δ4)
2. DHEA (Δ5)
SYNTHESIS OF TESTOSTERONE
- Age-related changes in hormone production
- Fetal – testosterone is the predominant hormone
- After birth – androsterone
- Puberty and throught out life – testosterone
- Secretion rate: 5 mg/day in normal adult male
(Transport)
- Binds testosterone and estrogen
- Higher affinity for testosterone
- Produced in the liver
- ↑By estrogen, liver disease, hyperthyroidism
- ↓By androgen, advancing age, hypothyroidism
Sex hormone-binding globulin (testosterone-estrogen-binding globulin)
TESTOSTERONE: TRANSPORT
- SHBG with albumin, binds 97-99 % of circulating testosterone
- Primary function is to restrict the free concentration of testosterone in the serum
- ↑ SHBG free E2/T ratio signs and symptoms of “estrogenization”
TESTOSTERONE: METABOLISM
- Oxidation at 17-position»_space; 17-ketosteroids (androsterone and etiocholanolone)
- Reduction of A ring double bond»_space; Dihydrotestosterone
- Aromatization»_space; Estradiol
- Active form in seminal vesicle, prostate, external genitalia, skin
- Reaction catalyzed by 5α-reductase
- Type I – predominantly expressed in the liver
- Type II – in reproductive tissues and peripheral targets
- 400 μg produced/day
Dihydrotestosterone (DHT)
- Stimulate testosterone production in Leydig cells by enhancing rate of cholesterol side-chain cleavage
Luteinizing Hormone
- Binds to Sertoli cells and promotes synthesis of androgen-binding protein (ABP)
- ABP – transport testosterone in very high concentration to site of spermatogenesis
Follicle Stimulating Hormone
- Produced by the Sertoli cells
- An inhibitor of FSH synthesis and secretion
- Contains an α and β subunit linked by disulfide bonds; two forms differ in their subunits (A or B), while their α subunits are identical
Inhibin
PHYSIOLOGIC EFFECTS (Testosterone)
- Sexual differentiation
- Development of secondary sexual organs and structures
- Spermatogenesis
- Anabolic metabolism and gene regulation
- Male pattern behavior
Target cells for Dihydrotestosterone
Prostate, seminal vesicles, external genitalia, genital skin
Target cells for testosterone
Embryonic Wolffian structure, spermatogonia, muscles, bone, kidneys, brain
PHYSIOLOGIC EFFECTS (Testosterone)
Affinity for receptor: DHT > T
Affinity for Androgen Receptor Element: DHT > T
(SYNTHETIC ANDROGENS)
- Slows catabolism by the liver
e. g. Danazol, Methandrostenolone, Stanozolol
Alkylation at 17α position
(SYNTHETIC ANDROGENS)
- Competes with DHT for binding to testosterone receptor
- Has progestational activity
Cyprosterone acetate
(SYNTHETIC ANDROGENS)
- Inhibitor of 5α-reductase
- Used in the treatment of Benign Prostatic Hypertrophy
Finasteride and Dutasteride
(PATHOPHYSIOLOGY)
- Due to testicular failure
Primary hypogonadism
(PATHOPHYSIOLOGY)
- Due to defective gonadotrophin secretion
Secondary hypogonadism
(PATHOPHYSIOLOGY)
- Defect in testosterone receptor
- Feminized external genitalia
Testicular feminization syndrome
- Due to increased DHT or testosterone particularly in older males
- Leads to difficulty in urination due to obstruction of the urethra
Benign Prostatic Hypertrophy (BPH)
FEMALE SEX HORMONES
- Estradiol (E2) - Primary estrogen from the ovaries
- Formed from testosterone - Estrone (E1) - Formed from androstenedione
- Estriol - Produced during pregnancy from the placenta
- Progesterone
FEMALE SEX HORMONES: BIOSYNTHESIS
- Formed by the aromatization of androgens
- Involves 3 hydroxylation steps
- Requires O2 and NADPH
SEX HORMONES: BIOSYNTHESIS (CELLULAR SOURCES)
- Source of androstenedione and testosterone
Theca cells
SEX HORMONES: BIOSYNTHESIS (CELLULAR SOURCES)
- Converts androstenedione and testosterone to estrone and estradiol
Granulosa cells
SEX HORMONES: BIOSYNTHESIS (CELLULAR SOURCES)
- Produces progesterone and some estradiol
Corpus luteum
PERIPHERAL AROMATIZATION OF ANDROGEN
For males
- Accounts for 80% of estradiol
- Contributes to “estrogenization” in cirrhosis, hyperthyroidism, ageing and obesity
For females
- 50% of E2 during pregnancy
- Major source of E1 in postmenopausal women
- Binds estradiol 5x less avidly than testosterone or DHT
- Little affinity to progesterone
Sex hormone-binding globulin (SHBG)
- Binds progesterone with equal affinity to cortisol
- Little affinity for estradiol, testosterone, DHT or estrone
CBG
FEMALE SEX HORMONES: SECRETION
- Rate of secretion of ovarian hormones varies during menstrual cycle
- No storage
Metabolism: Estrogen
- Liver converts estradiol and estrone to estriol
- Conjugated to glucuronide and sulfate
- Conjugated steroids do not bind to transport protein; excreted readily in bile, feces and urine
Metabolism: Progestins
- Actively metabolized by the liver; ineffective when given orally
- Major progestin metabolite in urine is sodium pregnanediol-20-glucuronide
FEMALE SEX HORMONES: PHYSIOLOGIC FUNCTIONS
- Maturation of primordial germ cells
- Development of tissue that will allow for implantation of blastocyst
- Provide hormonal timing for ovulation
- Establishment of milieu for the maintenance of pregnancy
- Provide hormonal influence for parturition and lactation
- Stimulates the size and number of cells by increasing the rate of synthesis of proteins, rRNA, tRNA, mRNA and DNA
- Vaginal epithelium proliferates and differentiates
- Uterine epithelium proliferates and glands hypertrophies and elongates
Estrogen
- Myometrium develops rhythmic motility
- Breast ducts proliferate
- Anabolic effect on bone and cartilage
- Peripheral blood vessels – vasodilation and heat dissipation
Estrogen
- Reduce proliferative activity of estrogen on vaginal epithelium
- Convert uterine epithelium to secretory
- Enhance development of acinar portion of breast glands
- Decrease peripheral blood flow»_space; ↓heat loss»_space; ↑body temperature (indicator of ovulation)
PROGESTINS
Estrogen vs Progestin
- Progestin and estrogen act synergistically although they are antagonist
- Estrogen stimulates production of progesterone receptors
HORMONAL CHANGES
Childhood
Low estrogen, low gonadotrophin
Puberty
Pulsatile release of GnRH»_space; stimulate LH and FSH»_space; ↑estrogen»_space; follicle ripens»_space; ovulation
MENSTRUAL CYCLE
Varies between 25 – 35 days (average of 28 days)
Phases:
- Follicular
- Luteal
- Menstruation
- FSH»_space; follicle begins to enlarge
- E2 levels low during 1st week but rises progressively; maximal level 24 hrs before LH peak
- LH peak precedes ovulation by 16-18 hrs»_space; end of follicular phase
- Very low progesterone level
FOLLICULAR PHASE
- 14 +/- 2 days in length
- Granulosa cells of the ruptured follicle forms corpus luteum which begins to produce progesterone and some E2
- E2 peaks midway through the luteal phase then declines
- Progesterone also increases and peaks
- Pituitary supplies LH for about 10 days (for maintenance of corpus luteum)
LUTEAL PHASE
If implantation occurs:
- Cytotrophoblastic cells of implanted embryo secretes hCG
- hCG stimulates progesterone synthesis by corpus luteum
If implantation does not occur:
- Corpus luteum regresses and menstruation ensues
- The average blood loss during menstruation is 35 mL with 10-80 mL considered normal
- An enzyme called plasmin tends to inhibit the blood from clotting
- Many women experience uterine cramps during this time (dysmenorrhea)
MENSTRUAL PHASE
(PLACENTAL HORMONES)
- Supports the corpus luteum until the placenta produces amount of progesterone sufficient to support pregnancy
- Peaks in middle of 1st trimester
- Basis for pregnancy test
- Human chorionic gonadotrophin (hCG)
(PLACENTAL HORMONES)
- Produced by corpus luteum for the 1st 6-8 weeks of pregnancy and later by the placenta
- Progestins
(PLACENTAL HORMONES)
- Estradiol, estrone and estriol gradually increase throughout pregnancy
- Estriol produced in largest amount
- Estrogen
Fetal adrenal produces __ which is converted to estriol by the placenta; goes to maternal liver, conjugated and excreted in the urine
DHEA and DHEA sulfate
Progesterone from placenta goes to the fetal adrenal for synthesis of __
cortisol
- Also called placental growth hormone or chorionic somatomammotrophin
- Has biologic properties of prolactin and growth hormone
PLACENTAL LACTOGEN
Placental Hormones and their Actions
- HcG - maintains corpus luteum
- Progesterone - maintains uterine lining; inhibits uterine contraction
- Estrogen - maintains uterine lining; stimulates mammary gland
- Placental Lactogen - stimulates mammary gland; supplies energy to fetus
- Parathyroid Hormone RP - increases blood Calcium
- Relaxin - softens cervix and weakens symphysis pubis
- Corticotropin Releasing Hormone - increase heart rate, blood pressure, blood glucose, and stimulates partuition
- Trigger for __ is unknown
- Oxytocin stimulates uterine contractility but do not initiate labor unless pregnancy is at term
- ↑Estrogen may increase number of oxytocin receptors
- When cervix dilates during labor, oxytocin release stimulated
- Plasma level of progesterone and estriol declines after placenta is delivered
PARTURITION
(MAMMARY GLANDS)
Estrogen - Responsible for ductal growth
Progestins
- Stimulate alveolar proliferation
- Inhibits milk production and secretion
MAMMARY GLANDS (Prolactin and Oxytocin)
Prolactin
- Increase rate of synthesis of milk proteins
- Initiates and maintains lactation
- Stimulated by suckling
Oxytocin
- Stimulates contraction of myoepithelial cells that surrounds alveolar ducts
- Also stimulated by suckling
- Cessation of menstruation; occurs at about age 53
- Loss of all follicle and ovarian estrogen production
- Substantial amount of estrone produced by aromatization of androstenedione
- Marked increased of LH and FSH
- Atrophy of secondary sex tissues – epithelium of lower urinary tract and vagina
- Bone mass decreases (osteoporosis)
MENOPAUSE
SYNTHETIC ESTROGEN
- Modifications to retard hepatic metabolism
1. Diethylstilbestrol
2. Mestranol
3. Clomiphene citrate
4. Nafoxidine/Tamoxifen
- Orally active synthetic nonsteroidal estrogen first synthesized in 1938
- Found to be a teratogen when given to pregnant women
- Limited use today due to increased risk for breast cancer
DIETHYLSTILBESTROL
- 3-Methyl ether of ethinylestradiol
- Was the estrogen used in many of the first oral contraceptives
MESTRANOL
- Estrogen in almost all modern formulations of combined oral contraceptive pills
ETHINYL ESTRADIOL
Competes with estradiol for hypothalamic receptors»_space; GnRH release is not restrained»_space; ↑LH, FSH»_space; multiple follicles mature»_space; can result in multiple pregnancies
CLOMIPHENE CITRATE
- Combines with estrogen receptor to form stable complexes with chromatin»_space; inhibits action of estradiol
- Used in the treatment of estrogen-receptor dependent breast cancer
NAFOXIDINE/TAMOXIFEN
- Derivative of tamoxifen
- Exert estrogen agonist activity in the bones while acting as antagonist in the reproductive tissues
- Used in the treatment of osteoporosis
SELECTIVE ESTROGEN RECEPTOR MODULATORS
- Group of phytochemical from plant with non-steroidal estrogen-like activity
- Found in legumes and are present in great amounts in soybeans
PHYTOESTROGENS
(SYNTHETIC PROGESTINS)
- Has minimal androgenic activity
- Used in oral contraceptives
19-Nortestosterone derivatives
(SYNTHETIC PROGESTINS)
- Inhibits ovulation when given IM
- Inhibits cell growth; used in the treatment of endometrial carcinoma
Medroxyprogesterone acetate
MECHANISM OF ACTION
- Hormones combine with intracellular receptors»_space; binds to specific region of DNA»_space; effect changes in rate of transcription of specific gene
- Crossover action of sex hormones
- Progesterone binds to androgen receptors
- Some androgens bind to estrogen receptor
MECHANISM OF ACTION
- Estrogen and progesterone receptors
*-COOH terminal portion – binds steroid hormones
*DNA binding domain – recognizes sequence:
AGGTCAnnnTG(A/T)CCT in ERE
GGTACAnnnTGTTCT in PRE
- Decreased ovulation and/or decreased hormone production
Primary hypogonadism
- Loss of pituitary gonadotropin function
Secondary hypogonadism
- XO karyotype
- Female internal and external genitalia
- Developmental abnormalities
- Delayed puberty
Turner’s syndrome
- Stein-Leventhal syndrome
- Androgen overproduction
- Hirsutism, irregular menses, decreased fertility, obesity
Polycystic Ovarian Syndrome
PATHOPHYSIOLOGY
Hydatidiform mole/Choriocarcinoma - Increased hCG
Leydig cell tumors/Arrhenoblastoma - Increased testosterone
Granulosa-Theca Cell Tumors - Increased estrogen
Intraovarian adrenal rest - Increased cortisol levels
HORMONES OF THE ADRENAL CORTEX
- The adrenal cortex synthesizes glucocorticoids, mineralocorticoids, and androgens
- It initiates its action by combining with specific intracellular receptors
- The hormone-receptor complex then binds to specific DNA regions to regulate gene expression
HORMONES OF THE ADRENAL CORTEX: Importance
- Glucocorticoids are essential for adapatation to stress
- Mineralocorticoids regulate sodium and potassium balance
LAYERS OF THE ADRENAL CORTEX
- Zona glomerulosa produces mineralocorticoids
- Zona Fasciculata and zona reticularis produce glucocorticoids and androgens
*All glucocorticoids have mineralocorticoid activity and vice-versa
- 21-carbon steroids that regulate gluconeogenesis
- Cortisol produced by the zona fasciculata predominates in humans
- Corticosterone produced by the zona fasciculata and glomerulosa is less dominant in humans
GLUCOCORTICOIDS
- 21-carbon steroids that promote sodium retention and excretion of potassium and hydrogen ions
- The most potent, aldosterone, is produced by the zona glomerulosa
MINERALOCORTICOIDS
The zona fasciculata and reticularis produce __ and the weak precursor androstenedione, which are converted to more potent androgens in extra-adrenal tissues
dehydroepinandrosterone
(Nomenclature)
All steroids have __
cyclopentanoperhydrophenanthrene ring
NOMENCLATURE
- Steroid hormones and their precursors and metabolites differ in number and type of substituted groups, number and type of double bonds, and stereochemical configuration
- Asymmetric carbons allow for stereoisomerism
HORMONES OF THE ADRENAL CORTEX
- Most adrenal cholesterol is esterified and stored in the cytoplasm
- Upon stimulation by ACTH or cAMP, an esterase is activated and free cholesterol is transported to mitochondria where CytP450 side chain cleavage enzyme converts cholesterol to pregnenolone
HORMONES OF THE ADRENAL CORTEX
- An ACTH-dependent steroidogenic acute regulatory (StAR) protein is essential for the transport of cholesterol to P450scc in the inner mitochondrial membrane
- Aminoglutethimide inhibits P450scc
- are found in the SER
- They convert pregnenolone to progesterone
3β-OHSD (3β-Hydrosteroid Dehydrogenase) and Δ 5,4-isomerase
17-Hydroxylase, 21-hydroxylase and 11β hydroxylase
17-Hydroxylase and 21-hydroxylase are SER enzymes
11β hydroxylase is in the mitochondria
- is hydroxylated at the C21 position to form
11-deoxycorticosterone (DOC), which is an active (Na+-retaining) mineralocorticoid
Progesterone
Hydroxylation at C11 forms __, which has glucocorticoid activity but is only 5% as potent as aldosterone in man
corticosterone
C21 hydroxylation is necessary for both __ activity
glucocorticoid and mineralocorticoid
In the zona glomerulosa, which does not have the smooth endoplasmic reticulum enzyme __, a mitochondrial 18-hydroxylase is presentt
17α-hydroxylase
__ can only be synthesized in the zona glomerulosa
aldosterone
__ synthesis requires three hydroxylases located in the fasciculata and reticularis zones of the adrenal cortex that act sequentially on the C17, C21, and C11 positions. The first two reactions are rapid, while C11 hydroxylation is relatively slow
Cortisol
If the C11 position is hydroxylated first, the action of
__ is impeded and the mineralocorticoid pathway is followed (forming corticosterone or aldosterone, depending on the cell type)
17`-hydroxylase
__ is a smooth endoplasmic reticulum enzyme that acts upon either progesterone or, more commonly, pregnenolone.
17α-Hydroxylase
__ is hydroxylated at C21 to form 11-deoxycortisol, which is then hydroxylated at C11 to form cortisol, the most potent natural glucocorticoid hormone in humans.
17α-Hydroxyprogesterone
The major androgen or androgen precursor produced by the adrenal cortex is__
dehydroepiandrosterone (DHEA)
__ production increases if glucocorticoid biosynthesis is impeded by the lack of one of the hydroxylases (adrenogenital syndrome)
Adrenal androgen
Most 17-hydroxypregnenolone follows the glucocorticoid pathway, but a small fraction is subjected to oxidative fission and removal of the two-carbon side chain through the action of __
17,20-lyase
Most DHEA is rapidly modified by adding sulfate in the __
*DHEA sulfate is inactive; sulfate removal reactivates DHEA
adrenal gland and liver
DHEA is really a prohormone since the actions
of 3β-OHSD and Δ5,4-isomerase convert the weak androgen DHEA into the more potent __
androstenedione
Reduction of androstenedione at the C17 position results in the formation of __, the most potent adrenal androgen.
testosterone
__ is the prersor of DHT and Estradiol
*Most estrogen in men is produced in non-endocrine tissues
Testosterone
SECRETION OF STEROID HORMONES
- There is little storage of steroids in the adrenal gland; most are released in plasma after synthesis
- Cortisol levels are highest in AM after awakening and lowest in late afternoon (diurnal rhythm)
HORMONE TRANSPORT IN PLASMA
- The main carrier is transcortin or corticosteroid-binding globulin (CBG) produced by the liver, whose synthesis is increased by estrogen
- Small amounts of cortisol are bound to albumin
EFFECTS OF GLUCOCORTICOIDS (GC)
- CBG-bound cortisol has a half-life of 1.5-2 hours while corticosterone, which binds less tightly, has a half-life of less than 1 hour
- Deoxycorticosterone and progesterone compete with cortisol for binding with CBG
- Aldosterone does not have a specific transport protein, but it forms a weak association with albumin
METABOLISM AND EXCRETION
- Glucocorticoids are reduced and conjugated at C3 by glucuronide, or to a lesser extent with sulfate, making it water-soluble
- 70% of conjugated steroids are urinated, 20% are defecated, and 10% exit the skin
METABOLISM AND EXCRETION
- Aldosterone is cleared by the liver and excreted through urine again via glucuronidation
- Androgens are excreted as 17-keto compounds
- Testosterone is converted by the liver to less active metabolites
THE BIOLOGIC ACTIVITY OF A STEROID DEPENDS ON:
- Its ability to bind to a receptor
- Concentration of free hormone in the plasma
* Cortisol, corticosterone, and aldosterone all bind with high affinity to the glucocorticoid receptor
* However, cortisol is dominant because of its high plasma concentration
* Cortisol synthesis is regulated by ACTH, which is regulated via negative feedback by CRH
THE RENIN-ANGIOTENSIN SYSTEM (RAS)
- Also called renin-angiotensin-aldosterone system (RAAS)
- Regulates electrolytes and blood pressure
- Primary hormone is angiotensin II
__ are sensitive to sodium and chloride levels in the blood
Juxtaglomerular cells
Renin release is stimulated by__
low water, sodium, and chloride levels
FACTORS THAT INFLUENCE RENIN RELEASE (STIMULATORS)
- Decreased BP
- Supine»_space; Erect
- Low salt levels
- β-adrenergics
- Prostaglandins
FACTORS THAT INFLUENCE RENIN RELEASE (INHIBITORS)
- High BP
- Erect»_space; Supine
- High salt levels
- β-adrenergic antagonists
- PG inhibitors
- K+, ADH, angiotensin II
EFFECTS OF GLUCOCORTICOIDS
- Increase glucose production by increasing delivery of amino acids from peripheral tissues and increasing gluconeogenesis
- Increase hepatic glycogen deposition by stimulating glycogen synthase
- Increase lipolysis in extremities
- Increase lipogenesis in face and trunk
EFFECTS OF GLUCOCORTICOIDS 2
- Increase protein and RNA metabolism
- Suppress immune response (lysis of lymphocytes)
- Suppress inflammation by :
- Decreased leukocyte activity
- Decreased fibroblast
- Increased lipocortins which inhibit phospholipase A2
OTHER EFFECTS OF GLUCOCORTICOIDS
- Maintain normal BP and cardiac output
- Maintain water and electrolyte equilibrium
- Mediate response to stress
EFFECTS OF MINERALOCORTICOIDS
- Stimulate sodium transport by the distal convoluted and collecting tubules
- Promote potassium, hydrogen, and ammonium ion secretion by the kidney
- In terms of mineralocorticoid effect, cortisol is less potent than aldosterone, but because of its high serum concentration, it also has significant mineralocorticoid activity
- Primary adrenal insufficiency
- Hypoglycemia, extreme sensitivity to insulin, stress intolerance, anorexia, wt loss, nausea, weakness
- Low BP, low GFR, Low ability to excrete excess water
- Salt craving
- Low sodium, high potassium in serum
- Increased skin pigmentation because of increased POMC activation
ADDISON’S DISEASE
- Glucocorticoid excess
- May also be due to increased pharmacologic use or pituitary adenoma
- Diurnal pattern of ACTH secretion is lost
- Thinning of skin, muscle wasting, osteoporosis
- Truncal obesity, buffalo hump
- Impaired resistance to infection
CUSHING’S SYNDROME
CAUSES OF CUSHING’S
- Excess alcohol intake can also cause pseudo=Cushing’s syndrome with hypertension, truncal obesity, and acne
- Hypercortisolism is manifested which is not suppressed by Dexamethasone
- Stopping alcohol resolves the symptoms
- Primary aldosteronism due to adenomas in the zona glomerulosa
- Hypertension, hypokalemia, hypernatremia, alkalosis
- Renal artery stenosis can lead to JG cell hyperactivity and elevate renin and angiotensin II, resulting in secondary aldosteronism
CONN’S SYNDROME
- Included in newborn screening
- Decreased cortisol, increased ACTH
- Increased adrenal androgens causing virilization and ambiguous genitalia (Adrenogenital syndrome)
CONGENITAL ADRENAL HYPERPLASIA
- Acts through chemical messengers (hormones) carried in the circulation by secretion into blood and extracellular fluid
- Cells must bear a receptor for the secreted hormone to respond
Endocrine system
- Linear peptide hormone that stimulates secretion of gastric acid by the stomach
- Released by G cells in the pyloric antrum and duodenum
GASTRIN
GASTRIN
- GAS gene is located on the long arm of the 7th chromosome
- Forms: gastrin-34 (“big gastrin”), gastrin-17 (“little gastrin”), and gastrin-14 (“minigastrin”)
- The numbers refer to the amino acid count
Function of Gastrin
Stimulates parietal cells of the stomach to secrete HCl
- Directly: binds onto CCK2/gastrin receptors on parietal cells stimulating them to secrete H+ ions
- Indirectly: binds onto CCK2/gastrin receptors in the stomach, which then responds by releasing histamine, which in turn acts in a paracrine manner on parietal cells stimulating them to secrete H+ ions
Function of Gastrin 2
- Gastrin causes chief cells to secrete pepsinogen, the zymogen form of the digestive enzyme pepsin
- Pepsinogen is converted to pepsin in a low pH envt and the HCl provides a suitable environment for its activity
Function of Gastrin 3
- Gastrin increase antral muscle mobility and trophic effect on GI tract - contraction of circular muscle of the stomach
- Gastrin induce production of pancreatic enzymes by acinar cells
- Gastrin increases gastric blood flow
Gastrin is released in response to certain stimuli:
- Stomach distension
- Vagal stimulation (mediated by the neurocrine bombesin, or GRP in the human)
- Presence of partially digested proteins esp. amino acids
Hypercalcemia
Gastrin release is inhibited by:
- Acid (primarily the secreted HCl) in the stomach (negative fedback)
- Somatostatin also inhibits the release of gastrin, along with secretin, GIP, glucagon and calcitonin
In the __, gastrin is produced at excessive levels, often by a gastrinoma (gastrin-producing tumor, mostly benign) of the antrum or the pancreas
- May have MEN I or multiple endocrine neoplasia type I. MEN I patients often have tumors of the pituitary gland (brain) and parathyroid gland (neck), as well as tumors of the pancreas.
Zollinger-Ellison Syndrome
- Comes from Greek chole, “bile”; cysto, “sac”; kinin, “move”; hence, move the bile-sac (gallbladder))
- Previously called Pancreozymin, is secreted by the duodenum
- Release digestive enzymes and bile from the pancreas and gallbladder - stimulating the digestion of fat and protein
- Acts as a hunger suppressant
Cholecystokinin (CCK)
- Evidence has suggested that it also induces drug tolerance to opioids like morphine and heroin
- Decreases analgesic effects of opioids
Cholecystokinin (CCK)
STRUCTURE OF Cholecystokinin (CCK)
- CCK is composed of varying numbers of AA (e.g. CCK33, CCK8) depending on post-translational modification of the CCK gene product, preprocholecystokinin
- CCK is similar in structure to gastrin
- Last five C-terminal amino acids are same as those of gastrin
- Tyrosine residue responsible for biologic activity
FUNCTION OF Cholecystokinin (CCK)
- Secreted by the duodenal mucosa when fat- or protein-rich chyme leaves the stomach and enters the duodenum
- Acts on the pancreas to stimulate trypsinogen, chymotrypsinogen (converted to trypsin and chymotrypsin in the duodenum), amylase and lipase
- Catalyze the digestion of fat, protein, and carbohydrate
FUNCTION OF Cholecystokinin (CCK) 2
- CCK increases production of hepatic bile
- Stimulates gallbladder contraction and the relaxation of the Sphincter of Oddi (Glisson’s sphincter) - delivering bile into the duodenal part of the small intestine
- Bile salts form amphipathic micelles that emulsify fats, aiding in their digestion and absorption
FUNCTION OF Cholecystokinin (CCK) 3
- As a neuropeptide, CCK mediates satiety by acting on the CCK receptors in the CNS
- In humans, CCK administration causes nausea and anxiety, and weakly decreases the desire to eat
- Peptide hormone, comprised of 27 amino acids(14 AA are homologous to glucagon)
- Produced in the S CELLS OF THE DUODENUM IN THE CRYPTS OF LIEBERKÜHN
- Secreted in response to low duodenal pH due to chyme, (contains HCl) entering from the stomach
Secretin
- ↓ acid secretion from the stomach by inhibiting gastrin release from G cells
- Stimulates bicarbonate from the liver, pancreas, and duodenal Brunner’s glands to buffer the acidic chyme
- Enhances the effects of cholecystokinin
- Promote the normal growth and maintenance of the pancreas
Secretin
- Derived from a 153-amino acid proprotein encoded by the - __ gene and circulates as a biologically active 42-amino acid peptide
- Synthesized by K cells in the mucosa of the duodenum and the jejunum
- receptors are seven-transmembrane proteins found on beta-cells in the pancreas
- Induce insulin secretion
- Type 2 diabetics are not responsive to GIP
Glucose-dependent Insulinotropic peptide (GIP)
- Polypeptide hormone secreted by M cells of the small intestine that increases GI motility and stimulates the production of pepsin
- Control of motilin secretion is unknown
- Studies suggest that an alkaline pH in the duodenum stimulates its release
Motilin
- act as non-peptide motilin agonists
- Used to stimulate GI motility
- Administration of a low dose of erythromycin will induce peristalsis
Erythromycin and related antibiotics
- Peptide hormone containing 28 amino acid residues and is produced in the pancreas
- Half-life of 2 minutes
Vasoactive Intestinal Peptide (VIP)
Vasoactive Intestinal Peptide (VIP): Functions
- Secretion of water and electrolytes
- Dilate intestinal smooth muscle and peripheral blood vessels
- Stimulate pancreatic bicarbonate secretion
- Inhibit gastrin-stimulated gastric acid secretion
- Found in the brain and some autonomic nerves
- A specific region of the suprachiasmatic nuclei (SCN), which is the location of the ‘master circadian pacemaker‘
- plays a key role in the mammalian timekeeping machinery
Vasoactive Intestinal Peptide (VIP)
- Found in the heart
- Causes coronary vasodilation and positive inotropic and chronotropic effect
- Research done for heart failure treatments
Vasoactive Intestinal Peptide (VIP)
- Rare endocrine tumor, usually originating in the pancreas
- Massive amounts of VIP cause profound and chronic watery diarrhea and dehydration, hypokalemia, achlorhydria (WDHA-syndrome or Pancreatic Cholera Syndrome), vasodilation, hypercalcemia and hyperglycemia
VIPoma (Verner Morrison syndrome )
- 14 amino acid peptide originally isolated from the skin of a frog
- Homologues in mammals called neuromedin B and gastrin releasing peptide
- Stimulates gastrin release from G cells
- Together with cholecystokinin it is the second major source of negative feedback signals that stop the eating behaviour
Bombesin
- is a hormone produced mainly by P/D1 cells lining the fundus of the human stomach and epsilon cells of the pancreas that stimulates appetite
- levels increase before meals and decrease after meals
Ghrelin
- Produced in the hypothalamic arcuate nucleus -stimulates the secretion of growth hormone from the anterior pituitary gland
- The __ receptor is a G protein-coupled receptor
- Counterpart of the hormone Leptin, produced by adipose tissue, which induces satiation when present at higher levels
- Increased in anticipation of a meal and suppressed after food ingestion
Ghrelin
- Produced in the adipocytes
- Signals the brain whether fat stores are sufficient
- Inhibit NPY synthesis
Leptin
- Most abundant neuropeptide in the brain
- Include pancreatic polypeptide, peptide YY and seminalplasmin
- Potent stimulator of feeding behavior
- Involvement in circadian rhythms, sexual function, anxiety responses and vascular resistance
NEUROPEPTIDE Y
- Found mainly in some neurons throughout the CNS and in the N cellslocated in the intestinal mucosa
- Released into the circulation after food ingestion
- Stimulates pancreatic and biliary secretions and colon motility
- Inhibits gastric and jejuno-ileum motility, gastric acid secretion
NEUROTENSIN
- Endocrine effects of neurotensin include reduction or elevation ofplasmaconcentrationsofprolactin,thyrotropin,luteinizing hormone, andgrowth hormone
- Neurotensin also influences the release ofCorticotropin releasing factorandACTHrelease from adrenal medulla
NEUROTENSIN
- Family of peptides structurally and functionally similar to substance P
- Potent, rapidly acting secretagogues and cause smooth muscle contraction and vasodilation
TACHYKININ
- Peptide composed of a chain of 11 amino acid residues
- Belongs to thetachykininneuropeptide family
- Deduced amino acid sequence of substance P is as follows: ArgProLysProGlnGlnPhePheGlyLeuMet(RPKPQQFFGLM)
- Released from the terminals of specific sensory nerves
- Found in the brain and spinal cord, and is associated with inflammatory processes andpain
SUBSTANCE P
PANCREAS
Serves two major functions:
- Exocrine (producing pancreatic juice containing digestive enzymes)
- Endocrine (producing several important hormones - Insulin, Glucagon, and Somatostatin)
Name of cells: __
Product: Insulin
% of islet cells: 50-80%
Function: lower blood sugar
Beta cells
Name of cells: __
Product: Glucagon
% of islet cells: 15-20%
Function: raise blood sugar
Alpha cells
Name of cells: __
Product: Somatostatin
% of islet cells: 3-10%
Function: inhibit endocrine pancreas
Delta cells
Name of cells: __
Product: Pancreatic polypeptide
% of islet cells: 1%
Function: inhibit exocrine pancreas
PP cells
- An alpha chain of 21 amino acids linked by two disulfide (S—S) bridges to a beta chain of 30 amino acids
- Synthesized as a preprohormone in the β cells of the islets of Langerhans
INSULIN
- Peptide is removed in the cisternae of the ER and packaged into secretory vesicles in the Golgi apparatus
- Protease activity cleaves the center third of the molecule, which dissociates as C peptide, leaving the amino terminal B peptide disulfide bonded to the carboxy terminal A peptide
INSULIN
Structure of Human Proinsulin.
Insulin and C-peptide molecules are connected at two sites by dipeptide links. An initial cleavage by a trypsin-like enzyme followed by several cleavages by a carboxypeptidase-like enzyme results in the production of the heterodimeric (AB) insulin molecule and the C-peptide
INSULIN
- Proteolysis of the C peptide occurs in the Golgi Apparatus and secretory granules
- Exocytosis of the granules releases insulin as well as the cleaved C peptide (inactive) into the bloodstream
- Proteolysis - breakdown of proteins or peptides into amino acids by the action of enzymes
- Insulin 2nd messenger: Tyrosine kinase
Medical relevance of C- peptide
- C-peptide levels may be ordered in a newly diagnosed DM Type I as part of an evaluation of the person’s residual beta cell function
- In DM Type II, may be used to monitor the status of a person’sbeta cellsand insulin production over time and to determine if/when insulin injections may be required
- useful for monitoring residual beta cell function in DM patients who are in insulin therapy
C- peptide Uses
- High levels of C-peptide generally indicate high levels ofendogenous insulin production - ↑ glucose intake and/orinsulin resistance
- Low levels of C-peptide are associated with ↓ levels of insulin production
*Occur when insufficient insulin is being produced by thebeta cellsor when production is suppressed byexogenousinsulin or with suppression tests that involve substances such as somatostatin
- Hormone binds to cell surface receptors resulting in a conformational change - activates kinase in the cytoplasm of the receptor
- Receptor phosphorylates itself and the activated receptor phosphorylates enzymes (Tyrosine kinase) that become activated or are inactivated upon phosphorylation
- Activation of receptor tyrosine kinases leads to rapid modulation in a number of target proteins within the cell
Insulin
GLUT Receptors and their locations
GLUT 1 – RBC, Brain; cell surface; allows constant glucose uptake into the cell
GLUT 2 – Beta islet cells, Liver, Kidney; cell surface; allows inc glucose hepatic uptake when blood glucose is high and vice versa
GLUT 1,4 – Skeletal muscle, Adipose tissue, Heart
*GLUT 4 – cell surface, specialized intracellular vesicles; insulin dependent
Insulin
- Secretion is regulated by plasma glucose levels
- ↑ uptake of glucose by β-cells leads to ↑ in metabolism - ↑ in the ATP/ADP ratio
- Leads to an inhibition of an ATP-sensitive K+ channel
- The net result is a depolarization of the cell leading to Ca2+ influx and insulin secretion
- Stimulates skeletal muscle fibers to take up glucose and AA convert it into glycogen and protein
- Liver take up glucose and convert into glycogen
- Acts on cells in the hypothalamus to reduce appetite
Insulin
- Inhibit production of enzymes involved in glycogenolysis
- Inhibiting gluconeogenesis
- conversion of fats and proteins into glucose
- Acts on adipose cells to stimulate glucose uptake and synthesis of fat
Insulin
Insulin Actions 1
- Chronic increases in other hormones (including GH, hPL, estrogens, and progestins), up-regulate insulin secretion
- Works by increasing the preproinsulin mRNA and enzymes involved in processing the increased preprohormone
- On the other hand, epinephrine and norepinephrine counter the effect of insulin in liver and peripheral tissue
- Both induce glycogenolysis and gluconeogenesis, which are hyperglycemic
Insulin Actions 2
- In other tissues insulin increases the number of plasma membrane glucose transporters
- In liver, glucose uptake is increased because of the enzymes glucokinase, phosphofructokinase-1 (PFK-1) and pyruvate kinase (PK) - the key regulatory enzymes of glycolysis
Insulin Actions 3
- Stimulates lipogenesis and fatty acid synthesis
- by promoting dephosphorylation and activation of Acetyl CoA carboxylase in a mechanism mediated by cAMP
- Diminishes lipolysis and increases amino acid transport into cells
Insulin Actions 4
- Stimulates growth, DNA synthesis, and cell replication
- Promotes glycogenesis
- by dephosphorylating glycogen synthase and activating it
- Inhibits glycogenolysis in the same manner as it regulates Acetyl CoA carboxylase
- Major function is to counter the action of hyperglycemia-generating hormones and to maintain low blood glucose levels
- Disorders associated with insulin generally lead to severe hyperglycemia e.g. Diabetes Mellitus
Insulin
- Inability to produce and/ or respond appropriately to insulin
- inability of the body to absorb and use glucose
- Result in a persistent elevation of blood glucose levels (Hyperglycemia) and other metabolic abnormalities that lead to the development of disease complications
Diabetes Mellitus
- Autoimmune-mediated destruction of insulin producing beta cells in the pancreas resulting in absolute insulin deficiency
- Insulin dependent DM
- Affects young persons
Type 1 Diabetes Mellitus
- Multifactorial syndrome with combined influence of genetic susceptibility and environmental factors (obesity, age, and physical inactivity) resulting in insulin resistance and impaired insulin production
- Other types of impaired glucose tolerance
Type 2 Diabetes Mellitus
- Stein-Leventhal syndrome
- Complex syndrome in women in the reproductive years where there is hypertension, hyperinsulinemia, obesity, anovulation and androgen excess commonly displayed as hirsutism
- Insulin resistance is present
PolyCystic Ovarian Syndrome (PCOS)
Syndrome X
- ↑ BP, dyslipidemia and ↑ waist circumference
- Probably caused by the insulin resistance of type 2 diabetes
- Essential hypertension, obesity, Type 2 diabetes, and Cardiovascular disease (CVD) develop
Metabolic Syndrome
Metabolic syndrome is present if you have 3 or more of the following signs:
- Blood pressure equal to or higher than 130/85 mmHg
- Fasting blood sugar (glucose) equal to or higher than 100 mg/dL
- Large waist circumference:
- Men - 40 inches or more
- Women - 35 inches or more - Low HDL cholesterol:
Men - under 40 mg/dL
Women - under 50 mg/dL - Triglycerides equal to or higher than 150 mg/dL
- A 29-amino acid polypeptide acting as an important hormone in carbohydrate metabolism
- Primary structure in humans is: NH2-His-Ser-Gln-Gly-Thr-Phe- Thr-Ser-Asp-Tyr-Ser-Lys-Tyr-Leu-Asp-Ser- Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu- Met-Asn-Thr-COOH
Glucagon
↑ Secretion of glucagon is caused by:
- ↓ Plasma glucose
- ↑ Catecholamines: Norepinphrine and Epinephrine
- ↑ plasma amino acids
- Sympathetic nervous system
- Acetylcholine
- Cholecystokinin
↓ Secretion of glucagon (inhibition) is caused by:
- Somatostatin
- Insulin
- Maintain blood glucose level - binding to glucagon receptors on hepatocytes, liver releases glucose (glycogenolysis)
- synthesizes additional glucose by gluconeogenesis in the liver
- Prevents the development of hypoglycemia
Glucagon
Glucagon also serves to:
- Increase free fatty acids and ketoacids
- Increase urea production
Glucagon
- Similar to insulin, glucagon lacks a plasma carrier protein
- Circulating half life is also about 5 minutes
- Principal effect of glucagon is in the liver –tissue 1st perfused by blood containing pancreatic secretions
Glucagon 2
- Glucagon binds its receptor in the plasma membrane of target cells (hepatocytes)
- Bound receptor interacts with G proteins, turns on adenylate cyclase
- Activated adenylate cyclase convert ATP to cyclic AMP - ↑ intracellular concentration of cAMP
- ↑cAMP in the cytosol make it probable that protein kinase A will be bound by cAMP making it catalytically active
Glucagon 3
- Active protein kinase A adds phosphates to other enzymes, changing the conformation and modulate the catalytic activity
- Levels of cAMP ↓ due to destruction by cAMP phosphodiesterase and the inactivation of adenylate cyclase
- ↑cAMP and PKA reverse all of the effects described above that insulin has on liver
- Very rare tumor of the islet cells causing abnormally-elevated glucagon levels
- Caused by pancreatic tumors (Glucagonoma)
- Sxs: Necrolytic Migratory Erythema (NME), ↑ amino acids and hyperglycemia
- History of Multiple Endocrine Neoplasia type 1 is common
Glucagonoma
- Secreted by δ cells of the pancreas
- 14–amino acid peptide, identical to somatostatin secreted by the hypothalamus
- In neural tissue, inhibits GH secretion and has systemic effects
Somatostatin
Somatostatin
- In the pancreas, somatostatin acts a paracrine inhibitor of other pancreatic hormones
- Somatostatin secretion responds principally to blood glucose levels, increasing as blood glucose levels rise and thus leading to down-regulation of glucagon secretion
- 36-amino acid peptide
- Product of the pancreatic F cells
- Secretion in humans is increased by a protein meal, fasting, exercise, and acute hypoglycemia
- Decreased by somatostatin and IV glucose
- Function unknown
PANCREATIC POLYPEPTIDE
