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TNTRODUCTTON TO ENDOCRTNOLOGY E HOMEOSTASIS ............maintains a constant internal environment. Appropriate responses to changes in external environment require precise coordination of the activities of body organs and of the individual cells that compose them. Coordination requires exchange of information . . , between the external environment and the organism; between the internal environment and tissue cells; between individual tissue cells. Thg essential information is mediated by neural and endocrine signals. Endocrine signals arise from I ClaSSical endoCrine Organs O diffUSe endOCfing CellS fgonads, adrenat, thyroid, pancreas........) ( in stomach, intesrine, kidney, heart........) Routes to coordination central: neuroendocrine control of most classical endocrine glands by the hypothalamus and pituitary gland. peripheral: more local neuroendocrine regulation of r components of some classical endocrine glands; , diffuse endocrine cells in the stomach, intestine, kidney and heart. &$ffi ffiil&ffis$ffie$"ffiNffiffitffigruffi ffi& ffiYffie Median eminence Anterior pituitary {lA Hormone* Secreted bv the Ant*Pi*r Fituitary u,,* ;a Bet,.r^t^.-, t a r^ ^^i',.i^E+ ^ rd6? \Ars a 0'^\r,6 Olhli.h6'- n'rhil^rra HORMONES E CUBIvTICAL NATURE Classical hormones fall into 3 categories: {. derivatives Of tyrOsine: er*,rNES (rhyroid hormones, catecholamines) {. derivatives of cholesterol: sTERoIDS (cortisol, oestradiol) * proteins and peptides: insulin, ACTH, oxytocin AnAmnS: epinephrine, norepinephrine, T3, T4 Derived from tyrosine Biological differences: TuynOID HORMONES cross cell membranes; intracellular receptors in blood, protein-bound stored in thyroid follicle CeTBcnoLAMINES do not cross membranes; cell surface receptors in blood, free or only lightly bound stored in membrane-bound granules SfnnOIDS: cortisol, oestrogen, vitamin D derived from cholesterol intracellul ar receptors in blood, protein-bound not stored in endocrine gland PrprrnES/PROTEINS peptides : ACTH, insulin glycoproteins: FSH, LH, TSH stored in membrane-bound granules in blood, often unbound cell membrane receptors Endocrine signals E Detected only by cells that have specific receptors to which the particular hormone will bind. Location of receptors Receptors may be located in the cell membrane or within the cell, mainly in the nucleus. Lipid-soluble steroids and thyroid hormones can pass through the cell membrane to interact with intracellular receptors, principally with nuclear receptors. Hormonereceptor complex activates a particular gene which is responsible for production of a protein that causes the hormonal effect. t I Hormones with low lipid solubility [e.g., peptide/protein hormones and catecholamines) interact with receptors in the cell membrane. The received signals are relayed by second messengers that induce enzymes present already within the cell to produce the characteristic response by the cell. Number of receptors At any time, the number of receptors depends on the balance between degradation and synthesis of receptors. A hormone may increase the rate of synthesis of the specific receptors in a target tissue: e.g., the increase ['up regulation') in LH receptors induced by FSH in the granulosa cells of the preovulatory follicle. Alternatively, a hormone may increase the degradation and/or decrease the synthesis of receptors in the target organ: e.9., GnRH can 'down regulate' its own receptors in the anterior pituitary , especially when the gonadotropes are subjected to constant stimulation by the releasing hormone rather than the physiological pulsatile stimulation. E CELLS HORMONES BINI} TO TARGET AUT'CRINE STIMULATION: hormone enters extracellular spaceandbindstoreceptorsonthecellthatproducesit. space hormone enrers extracellular near the producer cell' ,yprio"ated cell another to and binds stream and ACTIVITY: hormone enters blood *ARA.RTNB AcrrvrTy: ENDOCRINE binds to target cells Autocrine elselvhere l;. r ,. I - . Paracrine ,t. i oOo Coo sf8 td_ ffi THE CIASSICAI ENDOCRINE SYSTEM NEUROENDOCRINE SYSTEM: SALIENT FEATURES ANATOMICAL COMPONENTS HYPOTHALAMUS PITUITARY GLAND il$[ilfi,i:11'I,", THYROID GLAND PARATHYROID GLANDS GONADS PUTCENTA MAMMARY GLI\NDS REGULITTION OF HORMONE SECRETION Dominant role is played by the hypothalamus, which acts as a relay station where neural and hormonal messages are decoded and translated into appropriate signals to ensure the cooperation of the endocrine system with the nervous system in regulation of the peripheral endocrine glands. Hypothalamus contains many peptidergic neurons that function as nerve cells and as endocrine cells. Groups of nerve cells constitute the nuclei of the hypothalamus (e.9., the supraoptic and paraventricular nuclei). The peptidergic neurons use their electrical activity to release peptide hormones that regulate peripheral endocrine glands--some directly, others via trophic hormones from the anterior pituitary gland. TYPICAL PATTERN Hypothalamus. $_____-___ .tJ"""""""' .> Relpasing Hormone _--___________l """"""""""""'I HYPOTHALAMIC. PITUITARY AXIS ANATOMICAL COMPONENTS Hypothalamus Median eminence Pituitary stalk Pituitary gland: anterior and posterior lobes EMBRYOLOGY OF PITUITARY GTAND PosrenIoR L0BE : neural tissue.....downgrowth from brain......axons of peptidergic neurons extend from hypothalamic nuclei into this lobe.....released hormones formed in hypothalamus, not in posterior lobe ( e.g., oxytocin, vasopressinJ ArurrnIoR LoBE: glandular tissue.... upgrowth from primitive mouth.... various Wpes of epithelial cells, each secreting "its own" trophic hormone in response to specific regulatory hormone delivered by the portal blood supply [e.g., thyroidstimulating hormone in response to thyrotropin-releasing hormoneJ a Portal blood supply to anterior lobe Primary capillary plexus.....fenestrated vessels around top of pituitary stalk Portal venules .......running down pituitary stalk Secondary capillary plexus..... fenestrated vessels within the anterior lobe Secretory cells Peptidergic neuro[S......in discrete hypothalamic nuclei-) Epithelial cells in anterior lobe --> trophic hormones regulatory peptides Secretion by hypothalamic-pituitary axis Pulsatile secretion is absolutely essential for normal hypothalamicpituitary function. Information is transferred from hypothalamus to anterior pituitary by amplitude and frequency of pulses. A PULSE: a discrete burst of secretion of relatively short duration and modest amplitude. A SUHGE occurs when a sequence of frequent pulses, often of high amplitude, produces a massive increase extending over a period of some hours. Cell membrane receptors Nuclear recePtors Dendrites Uptake of signals:.. neural hormonal . Stimulatory inPuts exceed tfrreshold Nucleui Syntlresis of regulatorY peptide Generate action Potential CellbodY Axonal transPort Fenestrated caPillary Disehai'ge of regulatory PePtide Storage of regulatory peptide e I@^k ^"9 pgpnOencrc NEURON depicts: This diagrammatic representation of a typical (i) the uptake of neural signals by dendrites; iih ttr* uptake of endocrine signals by speeific receptors located either in the cell nfembfaire (for water-soluble hormones: peptides, proteins) or in the nucleus (for tiptC;dotuOle hormones: steroids, thyroid hormones); (iii,,ine-eadocrine response to signals (synthesis, transport and storage of regule{ory peptide}; (irjtr{tg *e*r^rui r""pon"" to signals (generation and conduction of action potential' *lrict is responsible for the discharge of the regulatory peptide). HYF#TE{ALA&€ g C-f ETE r gTdeffiY Ai{f Axons to primary capillaries Cell body Primary capillaries Median eminence Superior hypophyseal artery Pituitary stalk Portal venules \j Secondary capillaries Posterior pituitary Anterior pituitary tQJl Gontrol of the Anterior Pituitary by Hormores Secreted by the Hypothalamus Hormone Secretion: Pulses and Surges lSoo 2400 060 Time The inherent mode of secretion of hormones in the neuroendocrine system is pulsatile and it is controlled by an oscillator or pulse generator in the hypothalamus. The activity of the putse generator can be modulated both by neural inputs and by feedback signals from regutatory hormones, trophic hormones and/ or hormones secreted by peripheral endocrine cells. FEEDBACKLOOPS Peripheral effects of the hypothalamic-pituitary-peripheral gland system on such key homeostatic variables as blood concentrations of glucose, gonadal hormones or gonadotrophic hormones are subject to self-modulation by feedback on the activities of the hormones that regulate the variables. Appropriate adjustments may call for negative feedback or positive feedback. Some endocrine products are not regulated by feedback (..e., production of androgen by the adrenal cortex is stimulated by ACTH but the androgen does not effect the secretion of ACTH). Three types of complex feedback loops are recognized: . LoNc LooP: for example, gonadal hormones acting at the level of the brain and/or pituitary gland. . sHoRT LooP:e.g., pituitary gonadotrophins acting at the level of the hypothalamus. . uLTRA-SH0RT Loop: hypothalamic peptides acting at the level of the hypothalamus. The feedback effect of a particular hormone is not an intrinsic property of the molecule itself; for instance, although oestrogen is inhibitory (negative long loop feedback) during most of the menstrual cycle, it exercises an essential stimulatory effect (positive long loop feedback) shortly before ovulation. Clearly, the message conveyed by a hormone can vary depending on fluxes in frequency and amplitude of its secretion. NEGATIVE FEEDBACK a.:. Figure 5 . EHDOCRINE CELL HOHM6I.{E A HOBMONE B + : STIMUI-ATI0N . :INHIBITION tl} NEGATnIE FEEDBACK IN OPERAIION (a NEGATTYE FEEDBACK ATTENUATED Figtrres 5 & 6 " ffiega$re Fmdbaak Example l ffiffi ffi S*;g*#.'#:ffi8g"-o?3:'S?lf bythegran,rosacersorthe overiar. folllele ; the oestrogea exerts an inhibitory effeet on of FSI{ by the $mftary Sasd. tle release .. i:,: .P l\rurter' / . POSITIVE FEEDBACK ENDOCRINE CELL HOFMONEA HOHMONE B + :$TIMULATION Figure I i{ POSITI\E FEEDBACK IN {ri} INCRE.ASED TI1OPHIC OPERARON t' l .l I j STIMUI-ANON It- (iti) & 8 . Positiw. e Feedback Fi6g:eres 7 E:iample INCREASED POSITI1IB FEEDBACK : fhe gonad,otrophias FBH and LH ftlormone lll') stimulate the secretion of oestrogen I Herry.one B] by the graat{osa eells of the preornrlatory ovarian fotricle ( see Figure 21 )" Ee,e rryi&y ffiiffig d,Giit6ffif*tien of oestregen ( the "oestrogen s:!rger' ) stimu*ates the hypotiralam.us and ttre pittitary glaad to rBlease a srrge of g(}ee'€$6tffiSffils 6EEt n* iBbtHffiIE for oH:Iatioli. *:r: . i;:t:.:s i :li,r'al$ . .,r:..).! } ] ffiXTEHNAL CUES VTSUAU, AUD ITORY, OLFACTOHY, TACTILE + CENT TRAK hIERV vcg6 )TH*tAMU$ -r n ) SYST TEM 4+t' t ,f HUI! IORA NHUffiAt ,I PITUIT AHY / l' POSTHFIIOH ,LOBE & R k$ffiffi i \ .1,\J oxYrosrN I leoruanormop Fffi*$ffi **) .l'ARr ---'' GET al #RGiAN$ [ H$ffiMffWS GAMffiYH$ A# ACTIONS of HORMONES Stimulate ceII function [e.9., insulin stimulates glucose uptake) Inhibit cell function I e.g.,somatostatin inhibits secretion of growth hormone) Maintain the status quo [e.9., maintain blood calcium levels) Stimulate or inhibit cell division fgrowth or renewal of tissues or organs) Stimulate cell differentiation Stimulate or inhibit apoptosis [programmed cell death) Permissive role fHormone alters sensitivity of cells to the action of other hormones) HORMONE ACTING PERMISSIVELY ......when presence is necessary for , or permits, a biological response, even though the hormone does not initiate the response. MODE OF ACTION I Hormone alters sensitivity of cells to the action of other hormones. t May operate at level of receptors, intracellular messengers or effector systems. I Role often played by glucocorticoids and thyroid hormones. EXAMPTES Thyroid hormone [T3J enhances the effect of epinephrine on the mobilization of free fatty acids from adipose tissue. In the absence of cortisol, the lipolytic effects of catecholamines are negligible. In the absence of cortisol, the vasoconstrictor action of norepinephrine is compromised. Cortisol is required for full effect of glucagon on the regulation of glucose metabolism. HORMONE.HORMONE INTERACTIONS ) Synergistic effects :combined effect is greater than sum of individual effects. F Agonistic effects: two hormones have similar effects. F Antagonistic effects: two hormones have opposing effects. F Trophic effects: hormone stimulates development of another gland and secretion of that gland's hormones. F Permissive effects: one hormone allows another hormone to have its full effect. D Redundancy: crucial homeostatic variables (e.g., blood glucose, body temperature etc) are regulated by duplicative or overlapping controls, so that the same end result can be produced by different hormones from different sources (e.9., conversion of liver glycogen to glucose by glucagon from the pancreas and by epinephrine from the adrenal medulla). Biological significance: fail.ure of one mechanism can be compensatedby increased activity of another mechanism.