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HYPOTHALAMUS AND ITS HORMONES HORMONES OF THE PITUITARY Jana Jurcovicova ANATOMICAL NOTES Pituitary has a coordinating role in regulation of peripheral endocrine glands. It is connected with with part of diencephalon - hypothalamus to form hypothalamo-pituitary complex. Hypothalamus acts as a regulating and connecting center which enables the control of endocrine functions by central nervous system. Hypothalamus is located on the base of third ventricle and extends between - mammilary bodies (caudally) - optic chiasm (frontally) - optic tract (laterally) - thalamus (dorsally) On its base is median eminence, an important structure where converge regulatory pathways form hypothalamus into peripheral blood. BASAL VIEW OF THE HYPOTHALAMUS HYPOTHALAMO-HYPOPHYSEAL CONNECTION Central part of neuroendocrine regulation is hypothalamo-hypophyseal complex. Structural components of this complex are neurosecretory cells grouped into secretory nuclei located around the third ventricle. These secrete neuropeptides into portal blood connecting hypothalamus with adenopituitary. The other cell groups secrete neuropeptides to systemic circulation through posterior lobe via long axons of magnocellular hypothalamic neurons. Pituitary is located in sella turcica and is composed from 2 distinct structures adenopituitary and posterior pituitary arcuate nucleus and other nuclei adenopituitar hormones supraoptic and paraventricular nuclei posterior pituitary hormones ENDOCRINE HYPOTHALAMUS Hypothalamic secretory nuclei synthesize neuropeptides regulating adenopituitary secretion. These either exert either stimulatory or inhibitory effects. There are 4 stimulatory - releasing hormones and 2 inhibitory - statins releasing hormones: reproduction function activates gonadotropin releasing hormone - GnRH growth hormone activates growth hormone releasing hormone - GHRH thyroid function activates thyrotropin releasing hormone – TRH, adrenocortical function activates corticotropin releasing hormone – CRH. inhibiting hormones (statins) growth hormone inhibits somatostatin - SRIF (mild inhibitory activity also on TSH) prolactin inhibits prolactostatin - dopamine TOPOGRAPHY OF ENDOCRINE HYPOTHALAMUS The highest endocrine activity resides in medial hypothalamus (tuberal region), then lateral and proptic regions Medial hypothalamus: arcuate nucleus (ARC) containis GHRH, somatostatin and PIH, paraventricular nucleus (PVN) contains CRH and TRH. Periventricular nucleus contains somatostatin. Lateral hypotalamus: supraoptic nucleus (SON) contains neurohypophyseal hormons arginin-vasopressin (AVP or ADH) and oxytocin, suprachiasmatic jnucleus (SCN) which is a central pacemaker of daily rhythms Preoptic region is rich in GnRH. SCHEMATIC DRAWING OF HYPOTHALAMIC NUCLEI AC: anterior commissure PO: preoptic nucleus SC: suprachiasmatic nucleus OC: optic chiasma TC: tuber cinereum AP: anterior pituitary IN: infundibulum: posterior pituitary ME: median eminence AH: anterior hypothalamic nucleus SO: supraoptic nucleus TH: thalamus PV: paraventricular nucleus (not to be confused with periventricular nucleus, which is not shown) DM: dorsomedial nucleus VM: ventromedial nucleus AR: arcuate nucleus (associated with periventricular nucleus, which is not shown) LT: lateral nucleus PN: posterior nucleus MB: mamillary body SCHEMATIC CROSS SECTION OF HYPOTHALAMUS suprachiasmatic Guyton and Hall, 2006 Ganong and Hall, 2006 CROSS-SECTION OF THE ROSTRO - MEDIAL PART OF THE BRAIN CROSS- SECTION OF THE MIDDLE PART OF THE BRAIN HISTOCHEMICAL STAINING OF HYPOTHALAMIC NUCLEI HYPOTHALAMIC HORMONES SECRETED HORMONE abbr Thyrotrophic-releasing hormone (Prolactin-releasing hormone) TRH, PRH Parvocellular neurosecretory neurons Stimulate thyroid-stimulating hormone (TSH) release from anterior pituitary (primarily) Stimulate prolactin release from anterior pituitary Dopamine (Prolactin-inhibiting hormone) DA or PIH Dopamine neurons of the arcuate nucleus Inhibit prolactin release from anterior pituitary Growth hormone-releasing hormone GHR H Neuroendocrine neurons of the Arcuate nucleus Stimulate Growth hormone (GH) release from anterior pituitary Somatostatin (growth hormone-inhibiting hormone) SS, GHI H, or SRIF Neuroendocrine cells of the Periventricular nucleus Inhibit Growth hormone (GH) release from anterior pituitary Inhibit thyroid-stimulating hormone (TSH) release from anterior pituitary Gonadotropin-releasing hormone GnR H or LHR H Neuroendocrine cells of the Preoptic area Stimulate follicle-stimulating hormone (FSH) release from anterior pituitary Stimulate luteinizing hormone (LH) release from anterior pituitary Corticotropin-releasing hormone CRH Parvocellular neurosecretory neurons Stimulate adrenocorticotropic hormone (ACTH) release from anterior pituitary Magnocellular neurosecretory cells Uterine contraction Lactation (letdown reflex) Magnocellular neurosecretory neurons Increase in the permeability to water of the cells of distal tubule and collecting duct in the kidney and thus allows water reabsorption and excretion of concentrated urine Oxytocin Vasopressin (antidiuretic hormone) ADH or AVP PRODUCED BY EFFECT HYPOTHALAMO – PITUITARY CONNECTION Neurons of medial and preoptic hypothalamus end in the external layer of median eminence. Here they secrete neurohormones into primary plexus of portal vein system which converges along the pituitary stalk into the long veins. The neurohormones are then transported to adenopituitary secretory cells by veins of secondary blood plexus. The existence of releasing / inhibiting hormone dates back to early 70-ties of the last century, when in was first proved that adenipotuitary is regulated by humoral factors coming from the hypothalamus. Many neurohormones are produced also in GIT and are released into circulation. Therefore the concentration of releasing hormones in portal blood must be higher than in peripheral blood system. HYPOTHALAMO – PITUITARY CONNECTION HYPOTHALAMO-PITUITARY REGULATION DEVELOPMENT AND STRUCTURE OF PITUITARY diencephalon Rathke’s pouch of pharynx neural tissue ectoderm pars tuberalis pars distalis pars nervosa anterior posterior pars intermedia HYPOTHALAMO - PITUITARY SYSTEM Nc. paraventricularis Nc. supraopticus Hypothalamic neurons secreting releasing, inhibiting hormones (nuclei:nARC, mPOA NPE) Primary capilary plexus Chiasma opticum Neural lobe Portal vein Adenopituitary Anterior lobe Secretory cells Oxytocin Vasopresin ACTH, GH, TSH, LH, FSH, Prolactin INNERVATION OF ANTERIOR AND POSTERIOR PITUITARY BY NEURONES OF PARAVENTRICULAR AND SUPRAOPTIC NUCLEI STRUCTURES OF ARGININE VASOPRESSIN AND OXYTOCIN LIST OF PITUITARY HORMONES STRUCTURE OF PROOPIOMELANOCORTIN PC1 – PROHORMONE CONVERTASE1 PC2 – PROHORMONE CONVERTASE2 REGULALION OF ENDOCRINE HYPOTHALAMUS Feedback regulations Neural inputs - mainly from higher CNS centers Inputs from peripheral blood - leptin, ghrelin, insulin, cytokines , adenopituitary hormones, plasma levels of glucose, osmolality, steroid hormones (gonadal steroids and corticosteroids) Light - photoperiod for the synchronization of circadian rhythms Stress – various stress stimuli depending on the character of stressor FEEDBACK REGULATIONS REGULATION OF HYPOTHALAMIC HORMONES BY SHORT LOOP AND ULTRASHORT LOOP FEEDBACK REGULATION OF HYPOTHALAMIC HORMONES BY COMPLEX FEEDBACK SDDDDDDDDDDD NEURAL STIMULI OF THE HYPOTHALAMUS NEURON synaptic buttons myelin Ranvier cleft axon dendrites oligodendroglia nucleus mitochondrion vesicles with mediator exocytosis synapse postsynaptci receptots NEUROTRANSMITTER SYSTEMS REGULATING HYPOTHALAMIC SECRETION DOPAMINE nigrostriatal pathway SEROTONIN mesocortical pathway v tuberoinfundibular pathway NORADRENALINE NEUROTRANSMITTES REGULATING INDIVIDUAL RELEASING HORMONES Although many findings come from animal studies and cannot be applied to human physiology absolutely, the principal regulatory mechanisms are equal. It is generally accepted that central noradrenaline plays a pivotal role in stimulation of GHRH, CRH, AVP a TRH. The effect of noradrenaline on GnRH is unequivocal. Central serotonin stimulates the secretion of GHRH and also pituitary prolactin via its not yet known releasing hormone. Central dopamine participates in the inhibition of GnRH and in stimulation of CRH. CRH is also stimulated by acetylcholine. BLOOD BORNE STIMULI OF THE HYPOTHALAMUS BLOOD BRAIN BARRIER (BBB) Neurotransmitters and other molecules affecting neurosecretory activity of the hypothalamus (toxins, inflammatory agents) are found also in the circulation. Hypothalamus is protected from these influences by blood brain barrier (BBB). BBB is a complex mechanism regulating exchange of mediators between blood and CNS. It functions as protection from harmful stimuli (toxins) and also as transport system (for example glucose) into brain. BBB represented by tight junctions between endothelial capillary cells which are 100 times tighter than junctions in peripheral veins. These junctions are formed by ineractions of transmembrane proteins (claudins, occludins), adhesion molecules and cytoplasmic proteins (zona ocludens) bound to cytoskeletal actin filaments. BBB undergoes dynamic change during maturation, aging, under the influence of toxins or stress. For neuroendocrine secretion it is important that not all areas in brain are protected by BBB. These are: pineal gland, posterior pituitary, median eminence, and region around the third ventricle: area postrema, subcommissural organ, subfornical organ and organom vasculosum laminae terminalis BRAIN ENDOTHELIAL CELL – CELL TIGHT JUNCTIONS transmembrane molecules linked to actin skeleton adhesion molecules Engelhardt and Sorokin, 2009 AREAS WITHOUT BLOOD BRAIN BARRIER OVLT - organum vasculosum laminae terminalis; SFO – subfornical organ; ME – median eminence; SCO – subcomissural organ; PG – pineal gland; PL – posterior lobe; AP - area postrema; MODULATION OF ADENOPITUITARY RESPONSIVENESS TO HYPOTHALAMIC REGULATION HYPOTHALAMIC REGULATION OF FOOD INTAKE PHYSIOLOGY OF GROWTH HORMONE - GH INCREASES PROTEIN SYNTHESES DECREASES UTILIZATION OF CARBOHYDRATES IN MUSCLE STIMULATES OSTEOBLAST GROWTH AND IGF-I HIGH LEVELS ARE DIABETOGENIC STIMULATES IMMUNE SYSTEM REGULATION OF GROWTH HORMONE (GH ) SECRETION GROWTH HORMONE CHANGES DURING THE DAY Guytom and Hall, 2006 NORMAL FUNCTIONS OF GH PRODUCED BY THE BODY Main pathways in regulation of growth and etabolism Effects of growth hormone on the tissues is anabolic. Increased height during childhood is the most widely known effect of GH. Height is stimulated by at least two mechanisms: 1.Through receptor mechanism GH directly stimulates division and multiplication of chondrocytes and osteoblasts. 2.GH also stimulates the production of insulin-like growth factor 1 (IGF-1, formerly known as somatomedin C), a hormone homologous to proinsulin The liver is a major target organ of GH for this process and is the principal site of IGF-1 production. IGF-1 has growth-stimulating effects on a wide variety of tissues. IGF-1 is generated within target tissues, thus it is an endocrine and paracrine hormone. IGF-1 also has stimulatory effects on osteoblast and chondrocyte activity to promote bone growth. GH Increases calcium retention, and strengthens the mineralization of bone GH increases muscle mass through sarcomere hyperplasia GH promotes lipolysis, release of FFA from fat tissue and enhanced production of acetyl-CoA GH inncreases protein synthesis by increased transport of aminoacids into cells GH decreases glucose uptake in skeletal muscle and fat – hyperglycemic effect GH increases glucose production by the liver GH (in excess) promotes insulin resistance GH stimulates the immune system INSULIN-LIKE GROWTH F-1 (IGF-1) AND GROWTH IGF-1 [U/ml] 10 6 4 2 1 gigantism / acromegaly normal treatment - somatostatin GH-deficit (treatment – GH administration) PHYSIOLOGY OF PROLACTIN - PRL STIMULATES LACTATION (MILK PROTEIN CASEIN) STIMULATES IMMUNE SYSTEM (DIRECT EFFECT ON IMMUNE CELL PROLIFERATION) ANTIGONADAL ACTION (PROGESTERONE) HORMONE LEVELS DURING PREGNANCY AND LACTATION A- HCG B-ESTROGENS C-PRL D-PROGESTERONE EFFECT OF BREST FEEDING ON PRL RELEASE PRL levels in women after brest feeding on days 2, 4 ,6, post partum A- good lactation B- medium lactation C- poor lactation F - before feeding G - after feeding THE PINEAL GLAND Known over 2000 years Producing hormone of the night –MELATONIN It aggregates pigment granules containing melanin, and thus makes the skin lighter. Pineal gland EPIPHYSIS has a shape of a pine cone HISTOLOGY OF PINEAL GLAND The pineal is consists of connective tissue , blood vessels, glial cells, and pinealocytes (which secrete melatonin). Pinealocytes have larger, lighter staining nuclei glial cells have small darker staining nuclei. With age, calcified formations appear in the pineal gland (brain sand or corpora aranacea ). CIRCADIAN REGULATION OF MELATONIN PRODUCTION LIGH HINDBRAIN EYE EYE SPINAL CORD ß-adrenergic receptors N-acetyl transferases α -adrenergic receptors dark period Synthesis of Superior cervicale ganglion 24-HOUR SECRETION OF MELATONIN IN HEALTHY AND ARTHRITIC RATS pg/ml MELATONIN 250 200 150 100 50 0 ** ** MAEN AC MEAN cFA ** + ** 14 18 22 2 hour + 6 10 CIRCADIAN SYNCHRONIZATION CIRCADIAN OSCILATOR - SCN Principle of the circadian rhythmicity of the SCN are feedback mechanisms of clock genes SYNCHRONIZATION of the internal environment is the light/dark cycle Synhesis and release of melatonin is regulated from SCN, but synchronized by light/dark cycle. RHYTHM of melatonin secretion is indicator of CIRCADIAN PACEMAKER EFFECTS OF MELATONIN: improves quality of sleep activates immune system antioxidant (prevents oxidative stress)