Endocrine system Petr Vaňhara, PhD Department of Histology and Embryology Faculty of Medicine MU http://www.med.muni.cz/histology/petr-vanhara/ Intercellular communication Synaptic Autocrine Paracrine Endocrine Neurocrine Blood Blood Tissue Synapsis Distant Local Contact • Endocrine organs (e.g. pituitary, thyroid, parathyroid, adrenal) • Endocrine tissue within other organs (pancreas, gonads, kidneys, placenta) • Isolated endocrine cells (DNES, APUD) • Neuroendocrine cells General properties of endocrine organs • Common developmental scheme - invagination of epithelia, contact with original tissue lost during development - absence of exocrine ducts • C.t. capsule + septs • Trabecules of glandular epithelium, follicles or clusters of glandular cells or • Neurosecretory cells • Capillary network - Fenestrated capillaries - Sinusoids General properties of endocrine organs • Merocrine secretion - not only hormones – endocrine gland is sensu lato also liver Regulation of hormone secretion 1. Negative feedback by change of metabolic state Langerhans islets Insulin High glycemia Low glycemia 2. Negative feedback by increased concentration of secreted hormone Hypothalamus Adenohypophysis Adrenal cortex CRH ACTH Cortisol 3. Nerve system – direct innervation CNS (sympaticus) Adrenal medulla Adrenalin CNS Hypothalamus Neurohypophysis ADH  hormons are chemical messengers deliverd by bloodstream to target cells and tissues  chemical nature of hormone determines is function  classification  water soluble  water insoluble  surface receptors  nuclear receptors General properties of hormones • steroids – hydrophobic, intracytoplasmic or nuclear receptors (sex hormones, corticoids) • proteins and polypeptides – hydrophilic, plasma membrane receptors (insulin, pituitary hormones, PTH, …) • aminoacids and their amine derivatives (adrenalin, noradrenalin, thyroxin) General properties of hormones Testosterone Insulin FSH Adrenaline 4-[(1R)-1-hydroxy-2-(methylamino)ethyl]benzene-1,2-diol Growth hormone General signalling v General signalling Pituitary gland (gl. pituitaria)  hypothalamus  sella turcica  fossa hypophysialis  optic chiasm Pituitary gland (gl. pituitaria) Pituitary gland (gl. pituitaria) • adenohypophysis (pars distalis, pars tuberalis, pars intermedia) • neurohypophysis (pars nervosa) • infundibulum, eminentia mediana Pituitary gland (gl. pituitaria) • adenohypophysis - glandotropic hormones, prolactin, GH • neurohypophysis - hypothalamic hormones - ADH, oxytocin • anatomical and functional association with hypothalamus • capillary systems and neuroendocrine secretion Pituitary gland (gl. pituitaria) Hypothalamus • small region of diencephalon • complex neuroarchitecture • core of the limbic system • complex functions - regulation of temperature, emotions, eating behavior, circadian rythms - hormonal regulation controlled by various stimuli (osmoreception, concentration of nutrients, electrolytes, systemic functions - pain) • hypothalamic nuclei - n. supraopticus, n. paraventricularis - magnocelullar neurons - tractus hypothalamo-hypophysialis - parvocelullar neurons - capillaries in eminentia mediana CC NC Th PuGP Hyp SI Hypothalamo-hypophyseal system Mechanism of neurosecretion and the blood flow Tractus hypothalamo-hypophysialis - axons of magnocelullar neurons in nucleus supraopticus and paraventricularis - terminating on fenestrated capillaries in neurohypophysis - synthesis of prohormones  during axonal trasnportion maturation - capillary plexus from arteria hypophysialis inferior (branch of a. carotis interna  sinus cavernosus Hypophyseal portal system - parvocellular neurons e.g. in nucleus arcuatus, preopticus, paraventricularis and nuclei tuberales - axonal transport onto primary capillary plexus in eminentia mediana (from anterior and posterior superior hypophyseal arteries)  hypophyseal portal veins  secondary capillary plexus in adenohypophysis  inferior hypophyseal portal veins  vv. jugulares internae ncl. paraventricularis ncl. supraopticus Tractus hypothalamo-hypophysialis hypophyseal arteries anterior lobe secondary plexus of posterior lobe Capillary systems of hypophysis Eminentia mediana • elevated part of tuber cinereum, (detachment of infundibulum p. nervosa) • neurohemal area - hematoencephalic barrier is open here • fenestrated capillaries with large perivascular spaces Martin Heinrich Rathke (1793 – 1860) • Physician, anatomist,embryologist, zoologist • One of founding fathers of modern embryology "For a long time I have observed in several animals ... a small irregularly rounded depression which belongs to the mucous membrane of the mouth, of which it is clearly a thin-walled outpocketing. ... Finally I saw that this depression represents the first step in the formation of the pituitary gland" (p. 482). Rathke, H. : Ueber die Entstehung der glandula pituitaria. Arch, f . Anat,, Phys. und wiss. Med. S. 482-85. 1838 Embryonic development of pituitary gland • Ectoderm of stomodeum (Rathke’s pouch) • Neuroectoderm of ventral wall of diencephalon ~3rd week ~8th week ~16th week ~11th week ~6th week Embryonic development of pituitary gland ~6th week A = fossa B = hypothalamus C = eminentia mediana D = adenohypophysis Adenohypophysis (anterior lobe) Chromophilic cells Acidophils - Somatotropic (STH, somatotropin), 50% - Mammotropic (LTH, prolactin), 10-25% Basophils - Thyrotrophic (TSH), 3-5% - Gonadotrophic (FSH, LH), 10-15% - Corticotropic (POMC, ACTH, MSH), 15-25% Nonglandotropic - direct effect on target tissues Glandotropic - regulation of other endocrine glands Chromophobic cells • undifferentiated cells • degranulated (“empty“) chromophils • stromal cells Folliculo-stellate cells (FS-cells) Adenohypophysis (anterior lobe) Capillaries Acidophils Basophils Chromomphobes Adenohypophysis (anterior lobe) Acidophils producing GH Basophils producing glandotropic hormones ”FLAT PEG” • FSH • LH • ACTH • TSH • Prolactin • Endorphins • Growth hormone BASOPHILS PRODUCING GLANDOTROPIC HORMONES Pro-opio-melanocortin (POMC) rough ER  pre-prohormon produced by various tissues cleavage to • ACTH (target: adrenal cortex  kortisol) • MSH (target: melanocytes - mostly in paracrine way) • lipotropin (lipolysis, steroidogenesis) • endorphins ”FLAT PEG” • FSH • LH • ACTH • TSH • Prolactin • Endorphins • Growth hormone Corticotrophs hypofunction Corticotrophs hyperfunction FSH (folitropin), LH (lutropin) • gonadotropic cells of adenohypophysis stimulated by GnRH • glycoproteins, 30kDa • heterodimer, two noncovalent bound subunits (a/ - common for - LH, FSH, TSH, hCG, b/ - specific) • FSH receptor (testes, ovarium, uterus) G-protein coupled receptor - glycosylated extracellular domain of 11 leucine rich repeats specific to FSH - after ligand binding, activation of G-protein and cAMP signaling - alternative activation of MAPK cascade (ERK) - complex signaling response (prostaglandins, PLPc, NO) FSH LH ovarium follicle development (FSHR in m. granulosa cells) ovulation, development of corpus luteum, production of androgens in thecal cells testes spermatogenesis, FSHR in Sertoli cells production of testosterone in Leydig cells (expression of LHR) extragonadal FSHR in secretory endometrium of luteal phase uterus (endometrial functions, embryoendometrial interactions) uterus, seminal vesicles, prostate, skin... unknown function TSH, thyrotropin • thyrotropic cells of adenohypophysis stimulated by TRH • production of T4 (thyroxin) a T3 (triiodothyronin) by thyroid gland • glycoprotein, 28,5 kDa, heterodimer, two noncovalent bound subunits (a, b) • TSH receptor on thyroid follicular cells • G-protein signaling  adenylylcyklase  cAMP - cAMP  iodide channels (pendrin), transcription of thyreoglobulin, endo- and exocytic pathway • cross-reactivity with hCG  in pregnancy - alterations in synthesis of thyroid hormones (gestational hyperthyroidism) GH, somatotropin, growth hormone • somatotropic cells of adenohypophysis stimulated by GHRH (somatocrinin) • several molecular isoforms (alternative splicing), ~20-24 kDa • broad spectrum of target cell types and physiological circuits - transcription of DNA, translation of RNA, proteosynthesis - lipid use (fatty acid mobilization, conversion to acetyl-CoA) - inhibition of direct use of glucose, stimulation of glukoneogenesis - transmembrane transport of aminoacids - proteosynthesis in chondrocytes and osteoblasts, proliferation, osteogenesis • GHR in various tissues - RTK, JAK-STAT • somatomedins - small proteins (MW 7,5 kDa), IGF-like - produced by liver • various pathologies associated with GH Clinical links Hypophyseal tumors • compression of surrounding structures (optic chiasma) • hyperfunction of endocrine component - prolactinoma - galactorrhea - hypogonadism (alterations of GnRH) - gigantism - acromegaly - nanism Posterior hypophysis (neurohypohysis) nonmyelinated nerve fibers – axons of neurosecretory cells (c.a. 100 000) of hypothalamic nuclei (n. supraopticus and paraventricularis) pituicytes (neuroglia) - astrocyte-like (intermediate fialmets, GFAP) - local control of secretion from neuroscretory termini - Herring bodies – neurosecretory endings – dilatation close to capillaries Hormones - oxytocin (OT) - antidiuretic hormone (ADH, vasopresin) Oxytocin • nonapeptide • magno-cellular supraoptic and paraventricular nuclei of the hypothalamus • OR - G-coupled receptor • lactation reflex • uterine contraction • social behavior Vasopressin • nonapeptide • retention of water • effective in collecting duct and distal convoluted tubule (aquaporine translocations) • blood pressure regulation by affecting t. media • diabetes insipidus, hypernatremia, polyuremia Anatomy Microscopic anatomy Hormones and target tissues Anteriorlobe(adenohypophysis) pars distalis superior hypophyseal arteries  primary capillary plexus at eminentia mediana  hypophyseal portal veins  secondary capillary plexus trabecular epithelium in cords and clusters, reticular fibers; agranular folliculo-stellate cells with so far unclear function chromophobe s undifferentiated cells degranulated chromophilic cells stromal cells lack hormonal activity chromophils acidophilic nonglandotropic mammotropic cells smallpolypeptides dopamin (PIH)  PRF (?)  prolactin mammary gland in gravidity and lactations somatotropic cells somatostatin (GHIH)  GHRH  somatotropin (STH) directly liver and growth plates other tissues via somatomedins basophilic glandotropic corticotropic cells glycoproteins CRH  ACTH, MSH adrenal cortex  cortisol melanocytespars tuberalis thyrotropic cells TRH  TSH thyroid  thyroxin, T3 pars intermedia Rathke’s cysts gonadotropic cells GnRH  FSH (ICSH), LH gonads  androgens, estrogens, progesterone Posteriorlobe (neurohypophysis) eminentia mediana  infundibulum inferior hypophyseal arteries  capillary plexus in neurohypohysis nonmyelinated axons of hypothalamic neurons n. supraopticus, n. paraventricularis (tractus hypothalamohypophysialis), pituicytes smallpeptides ADH tubulus reuniens, ductus colligens t.media of vessels oxytocin myometrium of uterus during gravidity myoepithelium of lactating mammary gland pars nervosa Epiphysis (c. pineale) • epithalamus • c.t. capsule continuous to pia mater • thin c.t. septa • nonmyelinated nerve fibers • pinealocytes (95%, large, pale, round nuclei) • interstitial neuroglia (astrocytes, dark, elongated nuclei) • acervulus cerebri • melatonin • pinealocytes - star-like, modified neurons in trabecules - association with fenestrated capillaries - neurosecretory dilatations - nonvisual photoreception Epiphysis (c. pineale) Embryonic development of epiphysis (c. pineale) • thickening of caudal part of ependyma that does not contribute to development of choroid plexus at the roof of diencephalon • neuroectoderm Thyroid gland (gl. thyroidea) • Follicular cells  thyroid hormones (T3, T4) • C cells  calcitonin C.t. capsule, septs Lobes  lobuli - follicles Follicles (50 µm -1 mm) - separated by interstitial loose collagen c.t. - simple epithelium (flat to cubic, according to secretory activity) - colloid Capillary network from thyroid arteries Thyroid gland - follicles Thyroid gland - follicles Follicular cells and C-cells (parafollicular) C-cells Synthesis of T3 and T4 T3 synthesis from T4 • T4 half-life in blood 6.5 days, T3 2.5 (T4 is a reservoir for T3) • deiodination by tissue specific deiodinase enzymes generates T3 T4 synthesis in thyroid • sodium-iodide symporter transports two Na+ and one I- across the basement • I− is moved across the apical membrane into the colloid of the follicle. • thyroperoxidase oxidises 2 I−  I2. • thyroperoxidase iodinates the tyrosyl residues of thyroglobulin • (TSH) stimulates the endocytosis of the colloidal content • endocytic vesicles + lysosomes, lysosomal enzymes cleave T4 from the iodinated thyroglobulin • exocytosis thyreoglobulin triiodothyronin T3 tetraiodothyronin (thyroxin) T4 Canonical T3 pathway Alternative T3 pathway C cells of thyroid Calcitonin - inhibition of osteoclasts Neuroendocrine cells - pale staining - epithelial basis, under basal lamina no contact with colloid - derived from neural crest - associate with ultimobranchial body, (derivative of the 4th pharyngeal pouch) • endodermal proliferation of pharyngeal floor • hypobranchial eminence and foramen caecum • bilobed civerticulum • ductus thyreoglossus Thyroid development Parathyroid gland (gl. parathyreoidea) 6 mm, 130 mg c.t. capsule and septs Capillary network Cords and clusters of glandular cells - Chief - Oxyphilic - Adipose • Chief - most abundant - small cells (7-10µm, big nucleus - mildly acidophilic - PTH – calcium metabolism • Oxyphylic - large, polyhedral, - strongly acidophilic - round nucleus - glycogen Parathyroid gland (gl. parathyreoidea) Parathyroid gland (gl. parathyreoidea) Parathyroid hormone (PTH, parathormone, parathyrin) • 84 aminoacids • stimulates resorption by osteoclasts • enhances resorption of calcium and magnesium in distal tubules and thick ascending limb • enhances absorption in the intestine (via vD3) PTH vs. calcitonin • glandulae parathyroideae superiores from endoderm of 4th pharyngeal pouch • glandulae parathyroideae inferiores from dorsal process of 3th pharyngeal pouch - together with thymus descend to lower poles of thyroid • ectopic PTH gland in thymus or mediastinum Embryonic development of parathyroid gland Embryonic development of parathyroid gland c.t. capsule, septs capillary plexus Adrenal gland (corpus suprarenale) Adrenal development cortex - mesoderm - mesothelium, coelomic epithelium medulla - neural crest Adrenal cortex Adrenal cortex • Zona glomerulosa (1/10) - thin layer under capsule - relatively small cells in coiled glomeruli - not abundand lipid droplets - mineralocorticoids • Zona fasciculata (6/10) - radially arranged trabecules - lipid droplets in cytoplasm - glucocorticoids • Zona reticularis (3/10) - branched trabecules - small, acidophilic cells - lipofuscin - androgen precursors Adrenal cortex hormones • Steroids produced incortex = CORTICOSTEROIDS • Steroidogenic cells - SER, lipid droplets, mitochondria - mineralocorticoids - glucocorticoids • Aldosteron – zona glomerulosa • Kortisol – zona fasciculata • Androgens, estrogens, progesteron – zona reticularis Adrenal cortex hormones Clusters of glandular cells in reticular c.t. - chromaffin cells – modified postganglionic neurons - ganglionic cells - capillaries, venules, nerve fibers - adrenaline and noradrenaline Neural crest origin Adrenal medulla arteriae suprarenales (3)  arterial plexus in cortex under c.t. capsule  radially oriented fenestrated sinusoid capillaries continuous with medullar capillaries  medullar veins  v. suprarenalis Adrenal vascularisation three arterial regions 1) c.t. capsule and superior parts of cortex 2) radial capillaries of cortex continuing to medulla 3) medullar capillaries from aa. perforantes c.t. capsule z. glomerulosa z. fasciculata z. reticularis medulla cortical arteriole capsular arteriole capsular venule medullar artery capillaries of z. glomerulosa arteria perforans capillaries of z. fasciculata capillaries of z. reticularis venules of z. reticularis medullar capillaries medullar veins Stress Hypothalamus Adrenal cortex ACTH Kortisol - glycogen lysis - stabilization of glucose levels - suppression of immune system Pituitary gland Adrenal medulla Autonomic nerve system Adrenaline - blood pressure, vasoconstriction, heart rate… Fight or Flight Adaptation, regeneration Region (zone) Hormone Target tissue Hormonal effect Control Cortex Zona glomerulosa Mineralocorticoids (aldosteron) Kidney Increaed renal reabsorption of Na+ and water Synergic to ADH Excretion of K+ renin-angiotensin system, high level of K+ low level of Na+ Zona fasciculata Glucocorticoids (hydrocortison) Most cells Release of aminoacids from muscles and lipids from fat tissue, peripheral utilization of lipids, antiinflammatory effects Stimulation by ACTH Zona reticularis Androgens (dehydroepiandrosterone) Most cells In adult males not significant Children and women growth of bones, muscles, hematopoiesis Stimulation by ACTH Medulla Epinefrine, norepinefrine Most cells Increased heart activity, centrlaization of circualtion, bronchodilatation, glycogenolysis, regualtion og glycemia Sympaticus Adrenal hormones Langerhans islet of pancreas Paul Langerhans 1847 – 1888) Laguesse E. Sur la formation des ilots de Langerhans dans le panreas. Comptes Rend SocBiol 1893;5 (Series 9k.819-20 B-cells producing insulin Ab-anti insulin –Alexa Fluor A-cells producing glucagon Ab-anti glukagon –Texas Red Langerhans islets of pancreas Thank you for attention Petr Vaňhara, PhD Department of Histology and Embryology Faculty of Medicine MU http://www.med.muni.cz/histology/petr-vanhara/ pvanhara@med.muni.cz Comments and questions: