Key Functions of the endocrine system

• regulation of sodium/water balance(for control of blood volume/BP)
• regulation of calcium/phosphate balance
• regulation of energy balance, fuel mobilization, utilization and storage
• coordination of response to stress
• regulation of reproduction, growth and development

Peptide hormones

• largest class of hormones: pancreatic, pituitary, adrenocorticotropic, thyroid stimulation, and gonadotropin hormones
• aminco acid-derived homrones and synthesized from tyrosine(catecholamines and thyroid hormones) and synthesis restricted to only certain specialized cells (adrenal medula)

Steroid hormones

• synthesized from cholesterol(reproductive hormones, glucocorticoids and mineralcorticoids
• occurs in certain specialized cells(adrenal cortex, gonads, placenta)
• lipid soluble, require binding proteins

Membrane receptor Model

• fixed receptor model
• lipid insoluble hormones bind to cell-surface receptors located in the plasma membrane
• production of second messengers which activate the intracellular signals needed to ahieve the physiologic endpoints(cAMP, cGMP, intracellular Ca and tyrosine kinases)

Lipophillic receptor model

• steroid hormones
• nuclear receptor families
• steroid can come into cell and bind to ligand binding domain of steroid receptor(cytoplasm or nucleus)
• once bound the receptor activates and translocates to the DNA to cause transcription
• some cytosol ones have heat shock proteins bound that inhibit until steroid binds

Common types of receptor regulation

• receptor desenitization-loss of receptor responsiveness and internalization(short term)
• homologous regulation-hormone affects the transcription of its own receptor
• heterologous regulation -receptor number for hormone A is affected by presence of hormone b
• pathological alterations in receptor number or function also occur and are the basis of many endocrine dysfunctions 

Pituitary gland

• formed in early embryonic life from the fusion of two ectodermal outpocketings: the infundibulum(brain) origin and rathke's pouch(upward evagination of the oral ectoderm)
• Rathke's pouch(pharyngeal ep.) undergoes extensive proliferation to form the anterior lobe of the pituitary(adenohypophysis)
• Infundibulum projects outward to become the posterior lobe (neurohypophysis) (connected to hypothalamus by hypohysial stalk)
• post pit has pars nervosa and the anterior pituitary consists mainly of pars distalis

Blood Supply of Pituitary

• anterior pituitary has an extensive vascular system referred to as the hypophysial portal system
• arterial supply to the anterior and posterior lobes is largely independent
• there is no direct anatomical connect btw anter pit and hypothalamus, all communication flows btw the two via the portal system

Anterior Pituitary 

• the adenohypophysis produces and secretes at least 6 different peptide/glycoprotein hormones which can be subdivided into direct acting and trophic hormones
• direct acting= growth hormone(GH) and prolactin(PRL)
• trophic = ACTH, thryoid stimulation, folicle stimulating, and luetinizing hormone

Glycoprotein family

Anterior Pituitary

• consist of two peptide chains
• the alpha chain is similar in all of these hromones and the beta chains are distinct and determine structural and biological specificity
• LH, FSH, TSH, hCG

Somatomammotropin Family

Anterior Pituitary

• large single chain polypeptides
• there is substantial structural homology between Growth hormone and PRL, and some overlap in function 

Pro-oplomelanocortin(POMC) family

• cleaved from a large common precursor molecule(POMC) to form a group of diverse hormones
• ACTH and MSH(melanocyte stimulating hormone) are examples
• has an NTerminal fragment and a beta lipotropin fragment that get cleaved off to leave ACTH

Secretory Cell Types of 

The Anterior Pituitary

• somatotrophs(50%)- growth hormone(GH)
• lactotrophs(10-20%)- Prolactin (PRL)
• somatolactotrophs(less 5%)- GH and PRL (these hormones use cytokine receptors at target organ
• Corticotrophs (20%) adenocorticotropin(ACTH)
• Thyrotrophs(5%) thryoid stimulating hormone(TSH)
• gonadotrophs (5%) - luteinizing and folicle stimulating hormones (LH and FSH)

posterior pituitary secretions

• oxytocin and ADH
• sources are stimulation from supraoptic and paraventricular nuclei?

Panhypopituitarism

• pituitary tumor that destroys anterior pituitary(most common) and vission disturbances possible
• congenital dysfunction
• destruction of the hypothalmic hypophysial portal system by thrombosis or severe head injury
• decreased sec of glucocorticoids and thyroid hormone lead to weight gain, lethargy and energy loss
• reduction in gonadotropins cause decreased sexual function and devel
• dwarfism may result from childhood panhypopituitarism, characterized by drastically reduced development of growth

Hypersecretory pituitary Disorders

• gigantism and acromegaly
• somatotrophic tumor, temporal onset which can determine the effects of GH overproduction
• pre-adolescent tumors that occur prior to fusion of long bone epihyses usually lead to gigantism(increased height and length of long bones
• post-adolescent tumors usually result in acromegaly(enlargement of hands, fingers, feet, jaws, nose and vertebrae(may cause kyposis)

Posterior Pituitary 

• the neurohypophysis stores and releases secretory granules in response to neural stimulation from the hypothalamus in a process termed stimulus-secretion coupling
• axons from the supraoptic and paraventricular nuclei conect the hypothalamus and post pit via infundibulum
• two peptide hormones are secreted by the neurons of the neurohypophysis, oxytocin(paravent) and ADH(supraoptic)
• ADH prohormone is syn in the hypothalamus and cleaved and activated in posterior pit

ADH

• distal collecting duct it increases water reabs by increasing water permeability
• vascular smooth muscle it has a vasoconstriction effect that act in concert in regulating blood volume and blood pressure 
• activates AC in the kidney 
• the V1 receptors expressed in smooth muscle and activates Gq

Oxytocin

• myoepithelial cells of the breast-stimulation of milk ejection
• uterine smooth muscle- stimulates contraction during parturition
• controlled by nipple stimulation (requires consistent stimulation and can also be influenced by emotional status)
• distension of the cervix during child birth-oxytocin release is governed by a positive feedback look, a rare endocrine event

Diabetes Insipidus

• disease characterized by the overproduction of dilute urine due to inability of kidney to reabs water
• central(neurogenic) DI- defect in vasopressin syn or release(most common cause is head injury resulting in damge to pituitary stalk)
• nephrogenic DI- renal resistance to vasopressin, either due to a receptor or signaling defect
• nephrogenic is caused by chronic electroylte imbalances(Ca), certain drugs or genetic inheritance(rare and usually in males)

Syndrome of Inappropriate Secretion of ADH

• disorder of water retention due to high levels of ADH
• caused by a variety of CNS disorders, drugs or ectopic sources of ADH(lung tumors)
• physiologic effect on the plasma is hypo-osmolality and hyponatremia
• treatment with loop diuretics and or fluid restriction may alleviate some forms of SIADH

Regulator of endocrine growth

• growth hormone secreted by somatotrophs in ant pit
• promotes cell hypertrophy, mitosis, hyperplasia of cells, differentiation of bone growth cells and early muscle cells
• GH deficiency results in pituitary dwarfism
• GH excess results in acromegaly: progressive thickening of bones and soft tissues, growth of somatic tissues(skin, muscle, heart , liver, GIT)
• 22kDa GH(more common) and 20kDA GH
• pvGH bears 93% homology to hGH and polactin shars 16% 
• somatostatin is growth hormone inhibitory hormone (periventricular rgion) and GHRH is from the arcuate nucleus(calcium triggers release in somatotrophs)

Insulin-like Growth Factor 1

• release from hepatocytes after stimulation from hGH
• in turn can inhibit secretion from somatotrophs and also arcuate nuclues
• can also stimulate periventricular region to secrete somatostatin (GHIH)

Physiological functions of

Growth Hormone

• increased protein synthesis and deposition in tissues(begins in mins)
• stimulation of lipolysis in adipose tissue resulting in increased free fatty acids in blood, enhanced fat utilitzation for energy(several hrs) and accounts for ketogenic effect of GH
• decreased carbohydrate utilization(diabetogenic/anti insulin effect): decrease uptake of glucose inn sk muscle and fat cells, inc gluconeogenesis, increased insulin resistance
• conditions of fasting stim GH secretion and stress and exercise
• obesitiy and aging inhibit GH secreetion 

Growth Promoting Hormones

• somatomedins or insulin-like growth factors(IGF)
• IGF-1, principal mediator of growth promoting actions of GH
• Structural similarity btw insulin anad IGF-1
• IGF-2 similar actions to IGF-1, synthesis less dependent on GH
• Thyroid hormones, sex steroids, glucocorticoids, insulin 
• IGF-1 use tyroine kinase receptors and 2 does not?
• growth rate parallels plasma IGF-1 levels (used to measure growth)

Hypothalmic regulation of eating

• satiety center- ventromedial nucleus (VMN)
• hunger center-lateral hypothalamic area(LHA)

Leptin

• derived from greek word meaiing thin
• adipocyte secreted circulating protein
• product of obesity(ob) gene
• other sources-stomach, placenta, skeletal muscle, pituitary, bone marrrow
• regulator of food intake and energy expenditure
• deficiency can lead to morbid obesity
• tells hypothalmus to limit food intake and increase energy expenditure (tells us we are full)
• many people that are obese have high leptin levels but resistant to it (receptors)
• leptin and insulin are anorexigenic signals for hypothalamus: cause secretion of POMC and inhibit NPY/AGRP

Anorexigenic signals

• inhibiting appetite
• pro-opiomelanocortin(POMC)
• melanocyte stimulating hormone (α-MSH)-POMC- cleavage product that binds to melanocortin receptors(MC3R, MC4R) on downstream neurons which inhibits food intake(produce satiety)

Orexigenic Signals

• promoting appetite
• neuropeptide Y(NPY)
• agouti-related protein(AgRP) inhibits MC4R blocking action of MSH (melanocyte stimulation hormone)
• Ghrelin

Thyroid Gland Structure

• bi-lobed structure suspended from the trachea
• consists of sacs known as follicles, which are filled with a proteinaceous fluid(colloid)
• size of the follicles can vary, depending upon thyroid activity or during pathogenesis
• very vasculaturized tissue(blood flow/gram exceeds that of kidney)
• one of the largest endocrine organs and has large potential for growth(goiter)
• Thyroid stimulating hormone(TSH) from ant pit can induce growth of gland and syn of T3 and T4 hormones

Thyroid Hormone Biosynthesis

• Thyroxine(T4) and triiodothyronine(T3) are the major hormonal products of the gland
• hromones are iodine containing derivatives of the amino acid tyrosine
• normal production of T3 and T4 depends on suppl of dietary iodine, which is supplied by table salt and other sources
• specialized transporter brings iodine into cell and it then exits into colloid as it is oxidized by peroxidase (activate it)
• then attaches to thyroglobulin precursor(Tα)
• then binds MIT, DIT, to make T3 or T4 that stays bound (need peroxidase) 
• thyroid gland then expends energy to bring colloid droplet into cell and protease cleaves T3 and T4 off and the precursors MIT, DIT go back through cycle 
• Two DITs make T4 and a MIT and DIT make T3 (reverse T3 is another thing made in peripheral tissues that are inactive)

Iodine

• used for thyroid hormone synthesis
• rec intake of iodine is 1 mg/week or 150 micrograms daily for adults
• iodine is stored in the body mainly as orgaic iodine(thyroglobulin)
• only about 1/5 of ingested iodine can be utilized for thyroid hromone syn, while most is excreted in urine

Thyroid hormone Transport

In Blood

• less than 1% of the thyroid hormones are present in the blood as free, unbound (active) hromones
• bound hormones have a much longer half-life and can act as reservoirs until delivery to target tissues
• three carrier proteins for the thyroid hormones include: thyroxin-binding globulin(TBG)(carriers most), thyroxin-binding pre-albumin(TBPA), albumin 
• T3 only carried by TBG and Albumin

Conversion of T4 to T3

• 5' Monodeiodonase(MD) converts T4 to T3
• 5MD converts T4 to reverse T3 (inactive) if your thyroid hormone status is normal or high 
• the liver and kidney convert much of T4 to T3(80%)
• brain, CNS and placenta contain isoform specific 5'MDs that control T4 to T3 conversion
• thyroid tends to release more T4 than T3 to prevent large increase in circ T3 and drastic effects on target tissue(T3 more active)
• T4 half life 7 days and T3 half life 1 day

Thyroid Hormone Action

• thyroid hromone places role in development of CNS as well as generalized tissue growth by regulation protein synthesis(often synergistically w/ hGH)
• must be present for hGH to work(permissive)
• thyroid hormone can also act permisively in a number of growth processes
• classic effect of thyroid hormone is to increase energy metabolism and O2 consumption (calorigenesis)
• can also increase cardiac output by decresing vascular resistance
• other effects include increases in intermediary metabolism(carbs, fats prot) as well as sensitizing the CNS to catacholamines (can were you out 

T4/T3 cellular mechanism of action

• freely enters cell and nucleas and binds to thyroid hormone nuclear receptor (heterodimerizes with retinoid X receptor, vitA)
• causes gene transcription
• cardiovascular: increase CO, tissue blood flow, HR, Heart strength and respiration
• Metabolism: increases mit, Na/K pumps, O2 consumption, glucose abs, gluconeogen, glycogenolys, lipolysis, protein syn and BMR
• also affects CNS devel, Growth and other systems

Hypothalamic-hypophysial-thyroid axis

• hypothalamus secretes thyrotropin releasing hormone, which travels via the portal system to stimulate the thyrotrophs of the anterior pituitary by binding to Gq coupled receptor
• the anterior pituitary in turn secrets TSH which acts and the principal physiological regulator of the thyroid gland and stimulates thyroid hromone syn via GPRC binding and activation of the Gs/AC signaling pathway
• symp stimulation generally inhibits TSH secretion(warm climate also causes a decrease)

Thyroid Autoregulation 

• iodine deficiency: thyroid compenastes by reducing hormone production until sufficienty iodine is available
• TSH levels increase, hpertrophy of the follicular cells occurs sometimes leading to an iodine-deficiency goiter(the T3T4 ratio may increase as a compensatory
• iodine excess: increase in diet iodine will initially enhance hromone syn, but the thyroid then escapes from the iodine effect(Wolff-Chaikoff effect)
• the thyroid adjusts by reduce blood flow and sensitivity to TSH

Antithyroid Substances

• number of chemical substances inhibit thyroid hormone syn, and in sufficent doses can cause goiter(goitrogens)
• chemical goitrogens(used in hyperthyroid therapy): thiocyanate(decrease iodine trapping), perchloride(inhibits iodine transport), propylthiouracil(blocks oxidation and coupling)
• naturally ocurring goitrogens: turnips, cabbage, broccoli

Hyperthyroidism

• excessive thyroid hromone production(thyrotoxicosis) results in numerous symptoms related to its metabolic action
• Graves' disease(autoimmune) is a prevalent example of thyrotoxicosis
• immune system produces antibodies(TS-Ab[stim]) that bind to and activate the TSH receptor on the thyroid cells
• there is a strong familial link to graves disease and it is about 5 times more prevalent in women than mens
• symp nervousness, increased appetite, hypersens to heat, fatigue, weight loss, dyspnea

Hypothyroidism

• thyroid hormone deficiency results in the decline of energy metabolism and heat production
• symptoms include decreased appetite, weight gain, sommolence(12-14), fatigue and lethaargy
• skin may be infiltrated with a gelatinous fluid(mucopolysaccharides) causing a puffy appearance of the face, hands adn feet, a condition known as mvxedema

Hashimoto's Disease

• 90% of hypothyroidisms
• autoimmune is the foremost cause of hypothyroidism
• it is caused by attack from cytotoxic CD8 lymphocytes on the thyroid along with autoimmune antibody effects that inhibit thyroid peroxidas
• inadequate thyroid horm production in infancy can cause deficits in CNS and skel devel leading to a disease known as cretinism, which can result in both growth and mental retardation
• testing thyroid hormone levels soon after birth can greatly reduce devel abnormalities

Primary and Secondary Hypothyroidism

• primary is endocrine gland itself, the thyroid is deficient and cannot make T3, T4, causing TSH to be made in greater amounts becaue no feedback inhib
• Secondary is at the anterior pituitary so TSH levels are low which reduce T3 and T4(response to TSH is normal though because thyroid is fine
• tertiary is the problem is with the hypothalamus(rare)

Body Calcium

• 99% of Ca is present in the mineralized form (hydroxyapatite of bone)
• 1% is in the Plasma
• 40% of plasma calcium is bound to plasma proteins and non-difusable through cappilaries
• 10% is bound to various ECF anions and is non-ionized by diffusable
• 50% of plasma calcium is ionized and iffusible through cap wall

Osteoclast

• degrading brush border sealed by integrins on the sides
• proton pump acidifies the pit and lysosomal enzymes are also released
• actions are a slow process
• rank ligand receptor and 
• calcatonin receptor(cAMP pathway)

Phosphate Metabolism

• adult human body contains 600g of phosphate, 85% of which is in the skeleton
• inorganic phosphate in the ECF is mainly in the form of HPO4 and a minor fraction is in H2PO4- (bouth forms found mainly in intracellular comp)
• constant,  rapid exchange of ECF PO4^3- within the body and is needed for many cellular processes involved in enery metabolism, growth and other diverse functions
• PO4^3- is an important structural component of bone (mineral accretion= anabolic process)
• kidneys and bone are the major players in phosphate balance

Parathyroid Gland

• chief cells of the parathyroid gland synthesize and secrete PTH (peptide hormone derived from prohormone)
• release withmulated when plasma calcium concentration is low 
• Ca sensor in chief cells is a Gq GPCR whos signal inhibits PTH release
• cAMP and Mg (Gs linked) are the main stimulatory signals for PTH release

Effector Sites of PTH

• increase plasma Ca and decrease plasma PO4
• bone-rapid osteocytic effect via bone fluid movement, prolonged osteoclastic effect on resorption of mineralized bone
• effect on osteclasts is through osteoblasts
• kidney-PTH stimulates Ca resorption(rapid)
• GI-indirectly via VitD
• PTH receptor on target organs signals through Gs/AC and feedback reg through Ca plasma levels

Calcitonin

• CT is a polypeptide syn and secreted by parafollicular or C cells within the thyroid gland
• as plasma Ca goes up, secretion of CT goes up
• important in lowering Ca during bouts of hypercalcemia
• CT rapidly shuts off osteoclastic activity, inhibits osteoclast formation in a prolonged manner(more pronounced in infants/children)
• plays relatively minor role in the maintenance of plasma Ca in mature adults

Vit D biosynthesis

• UV light activates VitD precursor at skin (breaks steroid ring)
• liver hydroxylizes it to 25-hydroxycholecalciferal (feedback inhibitor after)
• at the kidney PTH hormone stimulates hydoxylation at the 1 position (1hydroxylase) making 1,25-dihydroxycholecalciferol
• if no PTH it hydroxylizes at the 24 position to inactivate it (kidney)
• active VitD activates more caclium binding protein(calbindin) in GI plasma membrane as well as speeds up Ca ATPase and alkaline phosphatase
• very slow and sustained type of effect
• has direct effects on osteoblasts to stimulate matrix syn and promotes mineralization (this is counterintuitive) 
• also necessary for normal bone resorption in response to PTH(permissive)

Integrative actions of other hormones in

mineral metabolism

• Gonadal steroids: estrogens and androgens are directly involved in the pubertal growth spurt and epiphyseal closure and in Ca balance/skeletal integrity in adult life (long bones especially affected)
• glucocorticoids-necessary for normal skeletal growth via permissive actions on growth and metabolism(in excess, cushings, adversely affect all target organs involed in Ca homeostasis
• thyroid hormones: for normal skeletal development and Ca balance
• growth hormone-directly affects bone growth, also influences bone, kidney and gut

Hypoparathyroidism

• Hypoparathyroidism results in decrease ECF Ca and increased PO4; 
• symptoms are increased neuromuscular excitability(tetany, CNS dysfunction)

Hyperparathyroidism

• increased PTH secretion results in hypercalcemia and hypophosphatemia
• symptoms are neuromuscular impairment(weakness, CNS dysfuntion), plyuria and nephrolithiasis(kidney stones). long term skeletal damage(severe demineralization)

Vit D Deficiency

• may result from dietary absencem lack of sunlight, renal or liver diseases affecting the appropriate hydroxylases
• symptoms sever bone demineralization, skeletal deformities, fractures, dental abnormalities
• may occur prior to epiphyseal plate closure in children(rickets) or after closure in adults (osteomalacia)

Osteoporosis

• net bone loss, common in women
• decrease in osteoblast activity or an increase in osteoclast activity(or both)
• revention= weight bearing exercise(lifestyle)

Osteopetrosis

• abnormal matrix deposition and thickening of bones
• usually attributed to decreased osteoclast activity
• malformation of bones, particularly long bones (bowed legs in infants/toddlers)

Osteogenesis Imperfecta(OI)

• genetic collagen defect(mild to severe)
• weak bones and frequent fractures
• many people who have it do not realize that they have OI

Adrenal Gland

• lighter colored layers that are derived from mesoderm, in close asociation the gonads, produces steroid hormones(ineralocorticoids and gluccocorticiods)
• medulla-dark inner layer derived from neural ectoderm, synthesis of catecholamines
• arterial blood supply flows from cortex to medulla and steroid conc in bloodstream
• fetal adrenal zone is in btw and syn estrogen precursors for the placenta during pregnancy

Adrenal Cortex

• zona glomerulosa: most outside, synthesizes aldosterone
• zona fascioulata: middle layer, gluccocorticoids(cortisol)
• zona reticularis: androgens(DHEA and androstenedione 
• medulla creates epinephrine 

Adrenal Medulla

• Serves as bridge btw the endocrine and symp nervous system
• chromaffin cells are structurally and functionally comparable to postganglionic neurons in SNS (adrenergic receptors)
• synthesize and secrete epinephrine and Norepinephrine(lesser extent)
• epinephrine producing cells make up the majority of medulla and stain weakly for chromaffin while norepi producers display strong reax

Catecholamine  Biosynthesis

• catecholamines are sny from tyrosine(derived from diet or via hepatic hydroxylation of phen)
• rate limiting step in this biosynthetic pathway is conversio of tyrosine to DOPA by tyrosine hydroxylase
• DOPA then goes to Dopamine and then to NE
• conversion of NE to EPI occurs only in chromaffin cells of teh adrenal medulla due to exclusive proecence of PNMT, which transfers a methyl group to NE 
• sympathetic stimulation; ACTH stimulate steps 1 and Dopamine to NE steps
• cortisol from adrenal cortex stimulate PNMT
• dopamine and NE have product feedback inhibition on tyrosine hydroxylase

Degradative metabolism of catecholamines

• catecholamines are rapidly removed from the circ and inactivated in the liver, kidneys and neural tissue in two enzyme processes
• methylation(COMT) found in high levels in endothelial cells, kidneys, heart, and liver -converts to metanephrine or normetanephrine
• oxidation(MAO)
• MAO converts the two to vanillymandelic acid that is excrete in urine free or sulfate, glucuronide conjugated
• also some reuptake and storage in neural tissue

VMAT1

• brings dopamine into chromaffin granule (H ion exchanger
• inside Dopamine is turned into NE by DBH
• NE then leaves to cytosol  in vessicles and can be converted to Epi by PNMT in vessicles
• calcium influx causes exocytosis of vessicles

α-adrenergic receptors

• α1 receptors widely dirstributed among many tissues and activate Gq-PLC- Ca second messenger pathway to exert diverse effects
• α2 prevalent mainly in presynaptic terminals and act to inhibit NE release at the terminals (local negative feedback)
• NE has a greater effect then EPI on these
• vasoconstriction, intestinal relaxation, iris dilation, bladder sphincter contractin, uterine contraction

β adrenergic receptors

• all three activate Gs/AC/cAMP cascade
• widely expresed in cardio(mostly epi), lung, uterus and intestine and have both excitatory and inhibitory effects
• β1 EPI=NE ; β2 EPI>>NE; β3 NE>EPI
• vasodilaion(β2), Bronchodilation(β2)
• mostly metabolic responses

Adrenal corticosteroid biosynthesis

• only adrenal cortex makes glucocorticoids and mineralcorticoids due to exclusive expression and functional zonation of key enzymes 
• basic precursor is cholesterol
• rate limiting step, which occurs in mitochondria, is the conversion of cholesterol to pregnenolone (cytochrome p450)
• rest of rx happen in SER
• 21 hydroxylase converts hydroxyprogesterone to deoxycortisol
• glomerulosa cells only cells with aldosterone synthase 

Regulation of steroid biosynthesis

• steroid hormones readily diffuse across cell membranes and are not stored
• z glomerulosa: aldosterone(mineral): renin-angiotensin system
• z. fasciculata: cortisol(glucocorticoid): ACTH
• z reticularis Dehydroepiandrosterone(androgens): ACTH

Adrenocorticotropic hormone

(ACTH)

• corticotropin, a polypeptide tropic hormone secreted by anterior pituitary
• derived from POMC produced by corticotrophs of anterior pituitary
• POMC-derived hormones regulated by corticotropin-releasing hormone(CRH)
• POMC cleaved to get ACTH, endorphins and melanocyte stimulating hormones
• both CRH (brings in Ca) and ACTH use GPRC/Gs receptors 

Biological Activity of 

Glucocorticoids and mineralcorticoids

• glucocorticoids regulate intermediary metabolism
• mineral corticoids regulate electrolyte metabolism
• there is some overlap in the biological activity of these 
• cortisol has equal effect as each
• dexamethasone is a synthetic glucocorticoid
• fludrocortisone is a synthetic mineralcorticoid

Glucocorticoids

• these hormones were initially named for their effects on glucose metabolism, they also affect many aspects of intermediary metabolism(carbs, lipids, proteins)
• glucocorticoids can have direct effects on intermediary metabolism, but more often they act permissively (with out them other things wouldnt work)
• cortisol is the most abundant in humans
• physiologic effects of cortisol include stimulation of gluconeogenesis and glycogenolysis in liver
• increased protein catabolism and lipolysis
• often used at supra-physiological doses as anti-inflammatory

Glucocorticoid receptor

• members of nuclear receptor family of TFs
• inactive form is cytoplasmic (atached to HSPs)
• activates upon binding of cortisol
• metabolic effects mediated via transcriptional activation of GR
• anti-inflammatory effects mediated via transcriptional repression

Mineralocorticoid receptors

• similar to GR. ligand-activated receptor
• expressed in epithelial tissues involved in electroylte transport(kidney, colon, salivary glds, sweat glds,)
• and non epithelial tissues(heart, vasculature, adipose tissue)
• 11β=HSD2 converts cortisol to cortisone so that it doesnt bind to MR(aldosterone receptor)
• aldosterone has slower rate of dissociation to MR vs cortisol, despite similar affinity

Pharmacological effects of glucocorticoids

• carbohydrate and protein metabolism: 
• stimulates HGP from glycerol and alanine
• increases hepatic gluconeogenesis
• decreases peripheral glucose utilization(anti-insulin action), increases protein breakdown/glutamine synthesis, activates lipolysis, net result is hypoglycemia 
• MOA might be upregulation of PEPCK, G6phosphatase, F2,6 bisphosphatase
• redistribution of body fat, cushing syndrome, includes fat accumulation in back of neck and face coupled with fat loss in extremities
• promotes lipolytic effects of gorwth hormone and beta receptors(inc in Free FA

Glucocorticoid effects on 

Cardiovascular system

• due to MC induced changes in renal Na
• MR activation on heart and vessel wall causes increase in BP and hypertension 
• cushings syndrome(hyperadrenalism): increased cortisol secretion activates MR/GR, net reusltion is hypertension. 
• hypoadrenalism leads to reduced responsiveness to vasocontrictors(NE, AngII)

gluccorticoids effect on immune system

• anti-inflammatory and immunosuppressive action
• inhibit leukocyte function
• decreases release of vasoactive and chemoattractant factors
• decrease secretion of lipolytic agents, proinflammatory cytokines, COX2, NOS2
• decrease extravasation of leukocytes to sites of injury

Aldosterone

• principal mineralocorticoid in humans
• rean distal colleting tubule is primary target, causes K excretion and NA reabs (H2O also reabs)
• effects achieved by inc in activity and expression of lumenal Na channels and basolaeral Na/K ATPases
• nonrenal targets include salivary glands, sweat glands, colon and heart

Aldosterone Secretion

• renin-angiotensin system
• ANG II is primary physiological regulator of aldosterone secretion
• ANG II is a potent vasoconstrictor
• increased plasma k and decreased Na also stimulates Aldo release by direct action of the glomerulose cells
• ACTH has a minor stimultory effect on aldo release, and is a trophic hormone(increases size of cells)

Addison's disease

• primary adrenocortical insufficiency
• failure of adrenal cortex to syn cortisola nd aldosterone
• causes impaired intermediary metabolism and weight loss, reduced tolerance to stress, hyperpigmentation(excess ACTH cross reacts with alpha MSH receptor), and hyperkalemia/hyponatremia
• addisons crisis is lifethreatening condition resulting from inability to cope with stress
• replacement therapy is required

Secondary adrenocortical insufficiency

• caused by inadequate ACTH release from anterior pituitary 
• cortisol production is impaired while aldosterone synthesis is fairly normal
• symptoms are similar to primary insufficiency(less severe) and hyperpigmentation does not occure

Cushings Syndrome

• result of excess glucococorticoid and androgen secretion form the adrenal cortex
• adrenal tumor: constitutive syntehsis of corticosteroids
• pituitary tumor: excess ACTH(cushings disease)
• hypothalamic dysfunction-excess CRH leading to elevated ACTH(rare)
• ectopic ACTH secretion tumor(common in lung carcinoma)
• centripetal obesity, hypertension, hyperglycemia, hirsutism, mooon face

Conn Syndrome

• hyperaldosteronism is an excess production of mineralcorticoids as ar esult of an adrenal tumor (primary) or excessive renin-angiotensin activity (secondary)
• excess aldo results in K depletion (hypokalemia) and possibly alkolosis and Na retention
• water retention leads to ECF expansion, edema, and hypertension 

Congenital Adrenal Hyperplasia

(CAH)

• CAH is an inherited defect in one or more of the enzymes required for steroidgenesis
• six known defects that result in partial or complete blockade of cortisol or aldostrone biosynthesis
• 21-hydroxylase defect is most common (blocks syn of cortisol and aldosterone from progesterone or hydroxyprogesterone)
• 11 beta hydoxylase defect (prevents conversion of deoxycortisol to cortisol)
• deoxycortisol do have some activity 
• net effect is accum of steroid precursors in the adrenal cells and elevation of ACTH(lack of feedback inhibition) causing hyperplasia of the adrenal cortex