Endocrine system INTERCELULAR COMMUNICATIONS Synaptic Autocrine Paracrine Tissue Synapsis Local Contact Distant Endocrine Neurocrine Blood Blood • Endocrine organs (e.g. pituitary, thyroid, parathyroid, adrenal) • Endocrine tissue within other organs (pancreas, gonads, kidneys, placenta) • Isolated endocrine cells (DNES, APUD) • Neuroendocrine cells • Common developmental scheme - invagination of epithelia, contact with original tissue lost during development - absence of exocrine ducts GENERAL PROPERTIES OF ENDOCRINE ORGANS • C.t. capsule + septs • Trabecules of glandular epithelium or follicles or clusters of glandular cells • Capillary network - Fenestrated capillaries - Sinusoids GENERAL PROPERTIES OF ENDOCRINE ORGANS 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 REGULATION OF HORMONE SECRETION  hormones are chemical messengers delivered 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, corticosteroids) • 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 Estradiol Adrenalin Growth hormone Melatonin hCG GENERAL PROPERTIES OF HORMONES ENDOCRINE GLANDS PITUITARY GLAND (GL. PITUITARIA)  hypothalamus  sella turcica  fossa hypophysialis  optic chiasm PITUITARY GLAND (GL. PITUITARIA) Chiasma opticum A. hypophysialis sup. Diaphragma sellae Dura mater ANTERIOR LOBE POSTERIOR LOBE INFUNDIBULUM HYPOTHALAMUS A. hypophysialis inf. A. hypophysialis inf. Sella turcica of sphenoid bone PITUITARY (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) • adenohypophysis (pars distalis, pars tuberalis, pars intermedia) • neurohypophysis (pars nervosa) • infundibulum, eminentia mediana PITUITARY GLAND (GL. PITUITARIA) • Ectoderm of stomodeum (Rathke’s pouch) • Neuroectoderm of ventral wall of diencephalon EMBRYONIC DEVELOPMENT OF PITUITARY GLAND ~ week 3 ~ week 8 ~ week 16~ week 11 ~ week 6 • 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 MARTIN HEINRICH RATHKE (1793 – 1860) ~6th week EMBRYONIC DEVELOPMENT OF PITUITARY GLAND A = fossa B = hypothalamus C = eminentia mediana D = adenohypophysis EMBRYONIC DEVELOPMENT OF PITUITARY GLAND HYPOTHALAMUS • small region of diencephalon • complex neuroarchitecture • core of the limbic system • complex functions - regulation of temperature, emotions, eating behavior, circadian rhythms - hormonal regulation controlled by various stimuli (osmoreception, concentration of nutrients, electrolytes, systemic functions - pain) • neurosecretion from hypothalamic nuclei - n. supraopticus, n. paraventricularis - magnocelullar neurons - tractus hypothalamohypophysialis - oxytocin and ADH through neurohypophysis - parvocelullar neurons - capillaries in eminentia mediana - statins and liberins regulating secretion from adenohypophysis through hypothalamo-hypophyseal portal system Tractus hypothalamo-hypophysialis - axons of magnocelullar neurons in nucleus supraopticus and paraventricularis - terminating on fenestrated capillaries in neurohypophysis - synthesis of prohormones  maturation during axonal transport - 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 MECHANISM OF NEUROSECRETION ncl. paraventricularis ncl. supraopticus Tractus hypothalamo-hypophysealis posterior lobe secondary capillary plexus of anterior lobe primary capillary plexus at e. mediana anterior lobe MECHANISM OF NEUROSECRETION • synthesis and transport of effector hormones from n. supraopticus and n. paraventricularis via tractus hypothalamo-hypohesialis to neurohypophysis • synthesis of liberins a statins, their secretion to capillaries of eminentia mediana and further transport through portal system to adenohypophysis Primary capillary at eminentia mediana Hypophyseal veins A. hypophysyalis inf. A. hypophysyalis sup. Hypophyseal portal veins Hypophyseal veins Capillaries of secondary plexus at pars distalis A. carotis int. CAPILLARY SYSTEMS OF HYPOPHYSIS • elevated part of tuber cinereum (detachment of infundibulum p. nervosa) • neurohemal area - hematoencephalic barrier is open here • fenestrated capillaries with large perivascular spaces EMINENTIA MEDIANA • Nonmyelinated nerve fibers - axons of neurosecretory cells (c.a. 100 000) of hypothalamic nuclei (n. supraopticus and paraventricularis) • Pituicytes (neuroglia) - astrocyte-like (intermediate filamets, GFAP) - local control of secretion from neuroscretory termini - Herring bodies – neurosecretory endings – dilatation close to capillaries • Hormones - oxytocin (OT) - antidiuretic hormone (ADH, vasopresin) NEUROHYPOPHYSIS (POSTERIOR LOBE) NEUROHYPOPHYSIS (POSTERIOR LOBE) NEUROHYPOPHYSIS (POSTERIOR LOBE) 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 (aquaporin translocations) • blood pressure regulation by affecting t. media • diabetes insipidus, hypernatremia, polyuremia HORMONES OF NEUROHYPOPHYSIS (POSTERIOR 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) • unclear function, putative stem cells • cytokine production ADENOHYPOPHYSIS (ANTERIOR LOBE) Capillaries Acidophils Basophils Chromomphobes ADENOHYPOPHYSIS (ANTERIOR LOBE) ADENOHYPOPHYSIS (ANTERIOR LOBE) Acidophils producing GH Basophils producing glandotropic hormones ADENOHYPOPHYSIS (ANTERIOR LOBE) ADENOHYPOPHYSIS – FUNCTIONAL LINK TO HYPOTHALAMUS ”FLAT PEG” • FSH • LH • ACTH • TSH • Prolactin • Endorhins • Growth hormone REGULATION BY HYPOTHALAMIC HORMONES • gonadoliberin  FSH a LH • corticoliberin  cortikotropin • thyreoliberin  thyreotropin • prolactin releasing hormone (?) prolactin • somatoliberin  somatotropin • follistatin FSH a LH • somatostatin somatotropin, TSH • dopamin prolactin Pro-opio-melanocortin (POMC) ADENOHYPOPHYSIS– HORMONES rough ER  pre-prohormon produced by various tissues cleavage to • ACTH (target: adrenal cortex  cortisol) • MSH (target: melanocytes - mostly in paracrine way) • lipotropin (lipolysis, steroidogenesis) • endorphins 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 ADENOHYPOPHYSIS– HORMONES 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) ADENOHYPOPHYSIS – HORMONES 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 ADENOHYPOPHYSIS – HORMONES ADENOHYPOPHYSIS – HORMONES Hypophyseal tumors • compression of surrounding structures (e.g. optic chiasma) • hyperfunction of endocrine component - prolactinoma - galactorrhea - hypogonadism (alterations of GnRH) - gigantism - acromegaly - nanism CLINICAL LINKS Corticotrophs hypofunction Corticotrophs hyperfunction CLINICAL LINKS Harvey W. Cushing 1912 1855 Thomas Addison Cushing’s syndrome PITUITARY GLAND SUMMARY 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 in adenohypophysis trabecular epithelium in cords and clusters, reticular fibers; agranular folliculo-stellate cells with so far unclear function chromophobes 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 CRH ACTH Cortisol Group A 20 150 900 Group B 45 430 760 Group C 30 230 400 To study the effects of the hypothalamo-pituitary-adrenal axis, groups of mice were injected with different hormones. Group A mice were injected with cortisol to mimic effects of Cushing’s syndrome. Group B mice were injected with hormone X. Group C mice were injected with a saline solution. Blood samples were later taken from the various groups and average hormone levels were measured and recorded in Table 1. Table 1. Levels of hormones (in nmol/L) found in blood sample taken from experimental mice groups. LFMUHISTO https://b.socrative.com/login/student/ • epithalamus • c.t. capsule continuous to pia mater • thin c.t. septa • non-myelinated nerve fibers • pinealocytes (95%, large, pale, round nuclei) • interstitial neuroglia (astrocytes, dark, elongated nuclei) • acervulus cerebri • melatonin EPIPHYSIS (C. PINEALE) EPIPHYSIS (C. PINEALE) EPIPHYSIS - ACERVULUS CEREBRI • pinealocytes - star-like, modified neurons in trabecules - association with fenestrated capillaries - neurosecretory dilatations - nonvisual photoreception EPIPHYSIS (C. PINEALE) • thickening of caudal part of ependyma that does not contribute to development of choroid plexus at the roof of diencephalon • neuroectoderm EMBRYONIC DEVELOPMENT OF EPIPHYSIS Anolis Parietal eye SphenodonSphenodon • 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 their secretory activity) - colloid Capillary network from thyroid arteries THYROID GLAND (GL. THYROIDEA) THYROID GLAND - FOLLICLES Follicular cells and C-cells (parafollicular) C-cells THYROID GLAND - FOLLICLES Capillaries around thyroid follicles FOLLICLES OF THYROID GLAND 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 Critical for brain development Metabolism (nitrogen balance, proteosynthesis, lipolysis) 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 THYROID GLAND – T3 AND T4 HORMONES THYROID GLAND – T3 AND T4 HORMONES 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) THYROID GLAND - CALCITONIN • endodermal proliferation of pharyngeal floor • ductus thyreoglossus originates between tuberculum impar and copula • bilobed civerticulum, lobus pyramidalis • obliterated d. thyreoglossus – foramen caecum • ectopic thyroid tissue EMBRYONIC DEVELOPMENT OF THYROID GLAND 6 mm, 130 mg c.t. capsule and septs Capillary network Cords and clusters of glandular cells - Chief - Oxyphilic - Adipose PARATHYROID GLAND (GL. PARATHYREOIDEA) • 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) • 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) PARATHYROID HORMONE (PTH, PARATHORMONE, PARATHYRIN) PTH vs. CALCITONIN • glandulae parathyroideae superiores from endoderm of 4th pharyngeal pouch • glandulae parathyroideae inferiores from dorsal process of 3rd pharyngeal pouch - together with thymus descend to lower poles of thyroid • ectopic PTH gland in thymus or mediastinum EMBRYONIC DEVELOPMENT OF PARATHYROID GLAND c.t. capsule, septs capillary plexus ADRENAL GLAND (CORPUS SUPRARENALE) cortex - mesoderm - mesothelium, coelomic epithelium medulla - neural crest ADRENAL GLAND DEVELOPMENT ADRENAL CORTEX • Zona glomerulosa (1/10) - thin layer under c.t. capsule - relatively small cells in coiled glomeruli - not so abundant 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 • Steroids produced incortex = CORTICOSTEROIDS • Steroidogenic cells - SER, lipid droplets, mitochondria - mineralocorticoids - glucocorticoids • Aldosteron – zona glomerulosa • Cortisol – zona fasciculata • Androgens, estrogens, progesteron – zona reticularis ADRENAL CORTEX HORMONE ADRENAL 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 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 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  Medullary cells influenced by cortical hormones ADRENAL VASCULARISATION 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 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 Chronic stress Paul Langerhans 1847 – 1888) ISLETS OF LANGERHANS Laguesse E. Sur la formation des ilots de Langerhans dans le pancreas. Comptes Rend SocBiol 1893;5 (Series 9k.819-20 On July 27, 1921, Sir Frederick Banting and Charles Best succeeded in isolating insulin from canine pancreases and thereby discovered the first effective treatment for diabetes mellitus. ISLETS OF LANGERHANS B-cells producing insulin Ab-anti insulin –Alexa Fluor A-cells producing glucagon Ab-anti glukagon –Texas Red ISLETS OF LANGERHANS HEALTHY DIABETES TYPE I CRH ACTH Cortisol Group A 20 150 900 Group B 45 430 760 Group C 30 230 400 To study the effects of the hypothalamo-pituitary-adrenal axis, groups of mice were injected with different hormones. Group A mice were injected with cortisol to mimic effects of Cushing’s syndrome. Group B mice were injected with hormone X. Group C mice were injected with a saline solution. Blood samples were later taken from the various groups and average hormone levels were measured and recorded in Table 1. Table 1. Levels of hormones (in nmol/L) found in blood sample taken from experimental mice groups. Why does a pituitary adenoma cause a patient to have an excess level of cortisol? Please choose from one of the following options. •It increased the size of the hypothalamus. •Its cells did not respond to CRH. •Its cells did not respond normally to cortisol. •It decreased the level of ACTH circulating in the body. Which of the following can result in a chronic increase in a patient’s ACTH and CRH levels? •Pituitary tumor. •Destruction of the adrenal glands. •Taking medicinal glucocorticoids, such as prednisone. •Hypersecretion of cortisol from the hypothalamus. According to the results of the experiment, which is the most likely identity of hormone X? Please choose from one of the following options. •CRH, because Group C’s concentration of ACTH and cortisol is lower than that of the control group. •ACTH, because Group B’s concentration of ACTH and cortisol is higher than that of the control group. •ACTH, because Group C’s concentration of ACTH and cortisol is lower than that of the control group. •CRH, because Group B’s concentration of ACTH and cortisol is higher than that of the control group. Which of the following would exacerbate the symptoms of Cushing’s disease? Please choose from one of the following options. •Somatic cells not responding to cortisol. •Taking a glucocorticoid receptor antagonist. •Radiation therapy to treat a pituitary adenoma. •Taking glucocorticoids to treat asthma. Thank you for attention pvanhara@med.muni.czComments and questions: