PHYSIOLOGY Dr.

Oribio HORMONAL CONTROL OF CALCIUM 11/27/12

KIDNEY - PTH & vit D reabsorption of Ca GIT Ca from diet Vit D - (calcitrione) absorption of Ca BONES - greatest reservoir,

In normal Ca levels PTH pathway is inhibited, low calcium levels PTH pathway inhibition is stopped. Vitamin D (anti PTH) Acts primarily on the small intestine, minor in the kidney Normal situation: inhibits PTH, stimulates CSR gene Vit D comes from same raw materials for steroid hormone (cholesterol)
cholesterol

- uses vit D for storage of Ca in bones

-uses PTH to release Ca

7 dehydrocalciferol

Ca
Sources of Ca: Diet If blood Ca is high, dietary absorption is low vice versa Stimulus: low Ca, will activate the GIT, kidney and bones to absorb or release Ca. Major hormone: Vit D (calcitrione) contribution to bone metabolism, significant in medullary thyroid cancer PTH (parathyroid hormone) activation of PTH stimulate Vit D synthesis

cholicalciferol (by UV rays in the skin)

25 hydroxycholicalciferol - hydrolation at postion 25 in the liver - rate limiting step - sends negative feedback to cholicalciferol to stop production

1,25 hydroxycholicalciferol

- hydroxylation at postion 1
- most active firm if Vit D

low Ca

PTH Calcium Sensing receptors (CSR) responsible for determining the levels of Ca. During normal Ca levels CSR senses a negative feedback signal to PTH gene causing inhibition of formation of PTH PTH gene is depressed pre proPTH production to PTH is decreased PTH released via exocytosis are decreased.

Disorders with Vit D deficiency Liver cirrhosis Kidney failure Dark skin After 25 year old Ca deposition stops PTH released from low Ca levels, goes to kidneys and bone Bone bone resorption release of Ca and phosphorous to blood. kidney acts on connecting tubules for renal reabsorbtion of Ca PTH stimulates convertion of 25(OH)CC to 1,25 (OH)2CC

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Vit D Effect on GIT and kidney Increase absorption of gastrointestinal cells and kidney of Ca Deposition of Ca to the bone by inhibiting PTH Gastrointestinal Tract When Ca in lumen enters the intestinal cells by pressure gradients, Ca in taken by calbindin protein that binds Ca then transport to serosa to the blood. This reaction is favoured by Vit D. 11/28/12 Physiology of Bone Bone cells Osteoclasts no PTH receptors Osteoblasts stimulated by PTH Has PTH receptors Causes resorption when blasts receives signal from PTH causing dissolution of bone, blasts will secrete cytokines
PTH

Osteoprodegerin stops the osteocyte dessolution Secreted by osteoblast, acts as adecoy of bone, then blast will attach again to the bone. Bone resoption is greater than bone formation Osteoporotic changes and structural abnormalities Check and countercheck to form balance by PTH and Vit D. Other hormones for bone resoption Gonadal hormone Estrogen in women (estrodiol 17 beta/ E2) anabolic hormone for formation of bone favouring GIT absorption of Ca affect the life span of osteoblast and clast, icreasing the survival rate of blast causing apoptosis of clast androgen in men favour bone formation like estradiol anabolic reaction are due to convertion of andtogen to estrogen, conveted to peripherally to estrogen

osteoblasts
monocyte colony stimulating factor (M-CSF) - from monocyte/macrophages - forming osteoclast

menopause causes osteoporosis (occurs after first 6 months after menopause) due to decreased esrodiol andropause - osteoporosis is more severe Glucocorticoids line of steroids from cortisol Decresed cortisol osteoporosis Favors bone resorption decreases GIT absorption of Ca inhibits renal reabsorption Cushings syndrome cortisol secreting hormone from adrenal glands intake of glucocorticoids transplant patients, asthmatic, patients with problem on immunity

RANKL - receptor activator for NF - ligand - causes fusion of osteoclast forming polykaryotic cell for bone dessolution via lysosomes Batch 2016 MDSK

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Hypothalamic Pituitary Relationship

Anterior pituitary gland: adenohypohysis glandular (adeno) dorsal out pouch of nasopharyngeal (rathkes pouch) secretes and produces hormones (will not secrete or produce hormone when severed from hypothalamus. Hormones (least to most needed for survival) Prolactin (PRL) Growth hormone (GH) Thyroid stimulating hormone (TH) metabolic activity Gonadal hormone (GnH) FSH and LH ACTH/ corticotrophin control aldosterone and cortisol to control fluid and electrolytes. Hierarchy of hormones: significance in disease destroying pituitary. Hormones least important are destroyed first. Posterior pituitary gland: neurohypophysis invagination of hypothalamus supraoptic and paraventricular nuclei of hypothalamus extensions of axon terminals Hormones are not created in the posterior pituitary gland, they are created in the hypothalamus and stored in the post. Pituitary. rich in capillary fenestrated network hormones are easily released. ADH/vasopressin water retention, *aldosterone Na retention Oxytocin breastfeeding, labor, female orgasm

ADH and Oxytocin secreted as preprohormones in the hypothalamus, becomes prohormone in endoplasmic reticulum and packed to the axonal terminal area and becomes hormones stored in vesicles. Signals originating from the hypothalamus, stimulate SON and PVN, by increasing Ca, releasing the hormones. Stimulus for release of ADH osmotic pressure Amount of solutes dissolved in solution balance between solute and solvent is disturbed dectected by osmoreceptors Water is low osmotic pressure is high Water is high osmotic pressure is low

Osmoreceptors ADH is released and targets kidney, causing reabsorption of water. Pituitary AXIS
secrets releasing hormones (RH) GHRH, GnRH, TSHRH, ACTRH stimulates all Ant Pituitary hormone except except prolactin - inhibited hormone by NT (dopamine) is pitutary stalk is cut prolactin will still be stimulated. stimulating hormone (SH) or tropic hormone primary organ causes physiologi effect causes negative feedback to ant pituitary and hypothalamus

hypothalamus tertiary (3)

anterior pituitary secondary (2)

peripheral organ primary (1)

*hyperprolactenemia in women- breast secretion of milk like substance - in men no secretion, mild symptoms * primary hypothyroidism problem with at the level of thyroid 2 hypothyroidsm problem at the level of ant ptiutary 3 hypothyroidsm level of hypothalamus is affected area

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12/4/12 Anterior Pituitary Hormones Basophils Corticotropes Thyrotropes Gonadotropes Acidophils Somatotropes Lactotropes Corticotropes Adrenal gland Divided into 2: Cortex stimulated Controlled by ACTH Layers: (GFR) Zona glumerulosa produces aldosterone (rennin-angotensin aldosterone-axis) Zona fasiculata and zona reicularis - produces:

When there is a problem in axis: Hyperpigmentation (increase MSH) - 1 hypoadrenalism/hypocorticolism ACTH are high because there is no negative feedback Effect of cortisol - Hormones that helps in increasing glucose (glucogenic) glucocorticoid Aldosterone - maintains Na balance (mineral mineralocorticoid) Adrenal androgen testosterone derivative

Thyrotropes

CRH (corticotropin releasing hormone) from hypothalamus

TRH

ant pituitary secrets TSH

ant pituitary - release ACTH

periphral gland (adrenal cortex)

cortisol (exerts negeative feedback) Adrenal androgens enters the axis of gonadotropes.

thyroid epithelium secretes T3 (main hormone)

TSH from group of hormone with and subunit Shares the same subunit as its neighbour gonadotropes (FSH and LH) subunit is different Some disorders are 1 TSH but have gonadal manifestations T3 metabolic active and most potent T4 - prohormone, broken down to

Medulla secretes catecholamines (epinephrine and norepinephrine)

produce T3. main determinant of T3 reflection of real activity of thyroid Gonadotropes

Without ACTH, cortex will atrophy, ACTH allow secretion of aldosterone that maintain viability cortex ACTH affects fasiculata and reticularis Before ACTH is produced raw material (propionomelanocortin) (POMC) prohormone of ACTH Also give rise to happy hormones (endorphins) and enkephalines which are opiods MSH melanocyte stimulating hormone (dark hormone)

GnRH

FSH/LH dictate whether you are in follicular phase of luteal phase how would ovary know what to signal the pituitary gland?

FSH/LH

fast pulse produces LH Slow pulse produces FSH

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stimulated gonads (ovary and testes) - estrogen and progesterone

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Somatotropes Lactotropes doesnt have and axis Controlled/inhibited by dopamine dopamine - inhibits - no peripheral hormone that causes negative feedback

Somatotropes
GnRH

GH

GH increases lipolysis increase FFA (produces ketone bodies), conserve protein and CHO GH is diabetogenic increases glucose level by: high FFA
high Acetyl CoA

prolactin

Stimulus of prolactin secretion: *given birth withdrawal of estrogen and ptogesterone with the removal of placenta *breast suckling (more potent) - also stimulates hypothalamus to secrete oxytocin cause myoepithelial cells to contract thus milk let down

gluconeogen esis high glucose

high glucose

liver low uptake of glucose by the skelata muscle and adipose tissue

breast milk Hyperprolactnemia cause: autonomous tumor in the anterior pituitary secreting prolactin not controlled by dopamine. Signs and symptoms: Women galactorrhea secretion of milk like substance of the breast with non lactating female Amenorrhea increased prolactin decreases GnRH low estrogen and progesterone Men infertility, decreased libido, erectile dysfunction hypogonadism low GnRH general: peripheral visson loss (bilateral hemianopsia) rhinorrhea (CSF leak) hydrocephalic manifestation headache

- secretes IGF 1 (insulin like growth factor) - causes growth of individual

high FFA

Counter regulation of glucose: Glucagon Cortisol Catecholamines GH ------- increases glucose levels Stimulus for GH to increase: 1. GHRH 2. Sleep stage 3 & 4 increase GH release 3. Circadian rhythm (diurnal) increase GH in early morning just before awakening 4. Hypoglycaemia 5. Exercise and starvation GH conserves protein and CHO (glucose) releaseing ketone bodies for energy Abnormalities Posterior pituitary gland Anti Diuretic Hormone Excess SIADH retain water, no edema More water than solute (Na) hyponatremia

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Paraneoplastic syndrome Seen in patients with malignancy Deficiency diabetes incupidus doesnt have ADH, urinates in liters and liters of clear color urine. seen in patients who went for surgery, transection of pituitary gland from hypothalamus

Disorders 1hyperthyroidism 1hypothyroidism 3hyperthyroidism 2hyperthyroidism Lab error/TSH resistance TSH N

Test results FT4

FT3

Growth hormone (depends on age) excess growing age pituitary giantism patients bones grow in vertical/axial adult (after epiphysial closure) - acromegaly bones will grow in acral manner/horizontal superorbital ridge hands tongue heart deficiency growing age pituitary dwarfism proportional dwarf (si Mahal) no mental retardation acrondroplasia (si Dagul) Laron dwarf high/normal GH, but problem with the receptor Levi-Lorain dwarf normal/high GH and receptor, problem with the IGF1 o Pygmy of africa adult adult growth deficiency syndrome decrease in heart size

Thyroid hormones basic thyroid tests TSH most important, most sensitive mirror of thyroid functioning FT4 free T4 FT3 least important TH are protein bound, the metabolically active are free form/unbound hormone Thyroid secretes 90% T4, and 10% T3 Ex.

Thyroid hormones are stored in as colloid. Raw materials for thyroid Iodine iodide, from diet, iodine should be mixed with the food before it is boiling because iodine can evaporate. Thyroglobulin (TG) manufactured by ER and GA o long chain of tyrosine residue (74)

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iodine trapping pulling iodine to the cell by: Na-I symporter pull iodine and Na together o Na is higher in blood and low in the cell (diffusion) o Iodine higher in cell than in blood Na-K ATPase system energy produced is used by iodine o Maintain Na concentration Iodine moves to apical side of cell Pendrin exchange system where Iodine is pumped out to the lumen (colloid) and Cl is pumped in. TSH favors Na-I symporters and Na-K ATPase Also facilitates TG synthesis Iodine oxidation Iodine (in the cell) travelling to the lumen Peroxidase oxidizes iodine to iodide Iodide will bind to TG Organification Via exocytosis TG goes to the lumen to be organized. Incorporation of iodine in position 3 and/or 5

Coupling MIT iodine in position 1 3,5 DIT iodine in 3 and 5 If one MIT pairs wit DIT = T3 3,5 3 triodothyronine 2 DIT = T4 3,5 3,5 tetraiodothyronine Unused MIT and DIT are recycled by deiodinase Removinf iodine in tyrosine residue Storage Iodinated thyroglobulin stay in the colloid Release Signal goes to the thyroid cell iodinized TG is engulfed and exoxytosed to the cell. T3 & T4 are cleaved from TG and exocytosed to the blood. 12/7/12 Thyroid Stimulating Hormone are lipid hormones bound to a protein: (TBG/thyroxin binding globin) for transport o 2/3 of TSH are bound to TBG Thyrox B prealbumin Albumin How does hormone enter the cell? Being lipid soluble they freely pass the cell membrane T4 needs to be converted to T3 (active form) o 5 residue is removed to produce 3,5 3 TIT by deiodinase Are sensed by nucleus (nuclear receptor Hormone receptor complex causing effect on transcription, producing mRNA that produces a needed effect of the hormone Thyroid Hormone high Na-K ATPase pump

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Increase activity of metabolism, thus we must provide raw materials for metabolism CHO metabolism high glycolysis, gluconeogenesis, and glucogenolysis CHON metabolism high protein synthesis spare protein FAT metabolism high lypolysis and beta oxidation Other essentials are used: Vitamin metabolism is high O2 consumption All organs in body increase activity in response to increased thyroid hormone

Skeletal muscle Stimulate bone resorption Prone to osteoporosis Parathyroid hormone Decreased parathyroid hormone, increase Ca levels Vit D decreased Adrenal gland Medulla increase TH increase catecholamine stimulate alpha cell to produce glucagon 12/10/12 Cardiac patients: sugar goes up, why? Stress activation of sympathetic NS catecholamines

Effects: Cardiovascular Increase CO because of increase heart rate tachycardia BP may not increase because there is low TPR because of vasodilatation for heat production Strength of cardiac contraction palpitation Respiration Increase respiration high O2 consumption because of increase O2 demand GIT Increase gastric motility Hyperdefecation no change in stool consistency, not watery, increase in no of times in defecating Muscular system Skeletal twitching and tremors Reproductive system Thyrotropic patients have decreased libido CNS Frontal increased stimulus decreased focus, poor memory Insomnia high metabolism

gluconeogenesis

cortisol

glucagon

Adrenal Glands (suprarenal glands) Adrenal Cortex: 3 layers Zona glumerulosa Zona fasiculata Zona reticularis

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3 pathway, (bidirectional) utilization of cholesterol

CROLHOLESTEROL

Cortisol production of glucose Also an immunosuppressant, check and balance of immune system, muting inflammatory system

zona glumerulosa zona fasiculata zona reticularis

Excess hyperglycemia - Immunocompromise prone to opportunistic infection (fungal and viral)

prenenolone

pregnenolone pregnenolol

11 deoxycorticolsterone

progesterone 17 hydroxypregnolol 17hydroxyprogesterone dehydroepiandrosterone (DHEA)

DHEAS (androgen) - in male it is negligible, In female, responsible for 2 sex characteristics Development of pubic and axillary hair Female libido May not be felt, significant when there is too much DHEAS manifest as masculinising features

corticosone

alodsterone - mineralocorticoid

11 deoxycortisol dehydroepiandrosulfate cortisol -corticosteroid (DHEAS) -adrenal androgen

Excess hirsutism growth of hair where ii is androgen sensitive, ex. Mustache & beard, chest, legs & back, thicker axillary hair,. Pyramidal shape of pubic hair - Increase libido - Musculinization mure developed muscle - Lower pitch of voice - Clitoral megaly - Hisutism + genital abnormality = virilization

Aldosterone reabsorption of Na

Excess no hyponatremia because wneh absorbing 1 mol of Na, there is also absorption of water - Na is diluted by water and so Na is not measurable as it will appear normal - You can measure K levels - Normal Na but hypokalemic - Manifestations: o Hypertension with hypokalemia, because of Na-K imbalance

Cushings syndrome endogenous Abnormality that involves excessive cortisol S/S - Cortisol o hyperglycemia o glucose intolerance - aldosterone o HPN o Hypokalemia Page 9

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o immunosupressed DHEAS o ammenorrhea

tyrosine Stimulated by hypothalamus (sympathetic) by acetylcholine dopamine

exogenous same manifestations of endogenous withdrawal of cause (ex. Drugs/pills) negative feedback to ACTH decreases and the cortex will atrophy, because there is no cortisol to provide negative feedback 12/11/12 Adrenal Medulla part of sympathetic and endocrine system (neuroendocrine system) - nervous catecholamines acts as Neurotransmitters - endocrine catecholamines acts as hormone for metabolism cathecholamines (epinephrine and norepinephrine) fight or flight response Produced in the medulla Epinephrine produced only in medulla Norepinephrine 30% in adrenal and 70% produced by post ganglionic nerve terminals or area Medulla is not essential to life because 70% of catecholamines are produced elsewhere PMNT (phenylethanolamine N-methyltransferase) only foud in the medulla - Converts norepinephrine to epinephrine raw material (for production of norepinephrine) - Tyrosine

norepinephrine

stimulated by cortisol

epinephrine stimulus: stress hypothalamus ACH medulla how does cortisol go to the medulla? Because of blood suppy, the cortex and medulla share the same blood supply, thus cortisol can go the medulla Epinephrine and norepinephrine released to circulation in response to a threat and goes to target organ for the desired effect, Endocrine effect provision of substrate in response to threat providing enough glucose, - Decrease utilization of glucose increasing ambient glucose - Increase glycogenolysisn and gluconeogenesis and increase lypolysis o Providing enough energy against the threatening stimulus. Endocrine system integrate 1 organ system to another system END.

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