Hypothalamus and adenohypophysis. Neuroendocrine regulation THALAMUS - NON-SPECIFIC NUCLEI - SPECIFIC SENSORY NUCLEI - SPECIFIC NONSENSORY NUCLEI - ASSOCIATION NUCLEI HYPOTHALAMUS - SYSTEM OF SEVERAL DOZENS OF NUCLEI - PARAVENTRICULAR - MEDIAL - LATERAL REGION HYPOPHYSIS - PARS DISTALIS (STH, PRL, TSH, FSH, LH,ACTH) - PARS TUBERALIS (FSH, LH) - PARS INTERMEDIA (MSH) HypothalamusVentrolateral medulla (heart, stomach) Amygdala (associative regions of neocortex, olfactory bulb, hippocampal formation, subcortical structures including brain stem) Hippocampus (associative regions of neocortex, thalamus, reticular formation nuclei, etc.) Nucleus solitarius (viscerosensory information– heart, lungs, GIT, blood vessels – baro-/chemoreceptors) Locus coeruleus (prefrontal cortex, N. paragigantocellularis – integration of external and autonomic stimuli – stress, panic) Orbitofrontal cortex (sensory perception, reaction to reward/punishment) Body temperature regulation Neuroendocrine regulation Appetitive behavior (hunger, thirst, sexual behavior) Defensive reactions Autonomic nervous system (modulation) Biorhythms and their regulation Lamina terminalis (blood, blood composition) Behavior Circumventricular organs CC – corpus calosum OC – chiasma opticum ac – commisura anterior pc – commisura posterior AP – area postrema CP – choroid plexus ME – eminentia mediana NH – neurohypophysis OVLT – organum vasculosum laminae terminalis PI – pineal gland/epiphysis SCO – subcommissural organ SFO – subfornical organ Eminentia mediana - Afferent sensoric organ - Functional connection of hypothalamus and hypophysis - Point of entry of some hormones from circulation (fenestration) – leptin - CONVERSION - HUMORAL FACTORS – HYPOTHALAMIC REGULATION NEURONS OVLT - Regulation of autonomous processes - Febrile regulation - Blood osmolality - Regulation of secretion of GnRH stimulated by estrogens Subfornical organ - Body fluid homeostasis - Blood pressure regulation (R for ANP and ATII) - Oxytocin secretion regulation Area postrema - Afference (n. vagus, n. glossopharyn-geus) - R for GLP-1 and amylin - Chemosensoric neurons with osmoR - „detection“ of toxins - coordinated regulation of blood pressure (R for ATII, ADH, ANP) Subcommissural organ - Mainly unknown function - R for neuropeptides and neurotransmitters - ? Production of somatostatin - „catching“ of monoamines from CSF Anatomical and functional connection of hypothalamus and hypophysis Neurosecretion SON – supraoptic nucleus PVH – paraventricular nucleus PeVH – periventricular nucleus Arc – arcuate nucleus LHA – lateral hypothalamic region Magnocellular and parvocellular neurons – neurotransmitters and neuromodulators Magnocellular neurons Parvocellular neurons Paraventricularnucleus Arcuatenucleus - Angiotensin II - Cholecystokinin (CCK) - Dynorphins - Glutamate - Nitric oxide - Oxytocin - ADH - Angiotensin II - GABA - ANP - CCK - GRP - neuromedin B - CRH - dopamine - Endocannabinoids - Enkephalins - Galanin - IL-1 - Neuropeptide Y - Nitric oxide - SST, TRH - VIP - Acetylcholin - GABA - Agouti-related peptid - CART - Dopamine - Dynorphin - Endocannabinoids - Enkephalins - Galanin, Galanin-like peptid (GALP) - Glutamate - GnRH - GHRH - Kisspeptins - Melanocortins, including ACTH - Neurokinin B - Pancreatic polypeptide - Prolactin - POMC - SST - etc. Hypothalamic hormones Hypothalamic hormones are secreted in eminentia mediana region and enter portal circulation via fenestrations Axons of oxytocin and ADH synthesizing neurons go through eminentia mediana region. Hormones are secreted in neurohypophysis PIH (prolactin-inhibiting hormone) = dopamine Environmental factors Neural stimuli Hormonal stimuli Synthesis and secretion of hypothalamic hormones Signal integration to regulate endocrine functions and to maintain hoemeostasis Thyreoliberin (TRH, thyrotropin-releasing hormone) Characteristics - Phylogenetically very old peptide (primitive vertebrates) - Central and peripheral effects Hypothalamo-hypophyseal axis - Regulation of TSH and PRL secretion (prolactinemia, galactorea) - No effect on other AH hormones secretion (exception – stimulation of GH secretion during acromegaly, liver diseases, anorexia nervosa, psychotic depression; stimulation of ACTH secretion during Cushing's syndrome) Other places of TRH synthesis/secretion - cortex cerebelli - Circumventricular structures - Neurohypophysis - Endocrine pancreatic cells - GIT - Heart (positive inotropy and chronotropy) - Neuromodulator function - Role in central thermoregulation Clinical significance - In the past – hyperthyroidis diagnosis (hypothalamic X hypophyseal causes) - Possible role in depression treatment, spinal muscular atrophy and amyotrophic lateral sclerosis - Treatment of some syndromes (West, Lannox-Gastaut, early infantile epileptic encephalopathy) Thyreoliberin - regulation of secretion - Neural control - Circadian rhythm (maximum between 21:00 and 5:00 and between 16:00 and 19:00, peaks in 90– 180 min intervals - Temperature (cold) – higher synthesis among people from colder regions in winter – together with autonomic nervous system (catecholamines) - Stress – TRH synthesis and secretion inhibition (indirect negative feedback loop between glucocorticoids and effect on hippocampus) - Starvation – TRH secretion decrease („saving“ energy); effect of leptin Cortikoliberin (CRH, corticotropin-releasing hormone) Characteristics -Important part of CNS stress response modulation -Group of related peptides (CRH, urocortin, urocortin II, urocortin III, urotensin, sauvagin) with different CNA distribution and CRH-R1 and CRHR2 affinity -Exclusively CRH-R1 corticotropic cells (AC) -CRH-1 – neocortex, cerebellar cortex, subcortical structures of limbic system, amygdala, ovaries, endometrium, skin -CRH-binding protein Hypothalamo-hypophyseal axis - Fast ACTH secretion Other places of CRH synthesis/secretion - Limbic system - Amygdala, substantia nigra - Nucleus tractus solitarius - Parabrachial nucleus - Placenta (3rd trimester) - Lymphocytes, autonomic nerves, GIT - Cardiovascular system - Behavior, fear, anxiety regulation - Anorexigenic factor - Increased sympathetic tone Clinical significance - Potential treatment of obesity - CRH-R1 antagonists – anxiety and depression treatment - Blood pr. regulation (decrease) - Negative chronotropy - Immune system, reproduction Corticoliberin – regulation of secretion - Neural control – various stressors - Hypothalamo-hypophyseal axis activation - Sympathoadrenal axis activation - ADH and oxytocin binding - Ensuring requirements in emergency situations - Inflammation and cytokines - IL-1B and hypothalamo-hypophyseal axis activation - Circadian rhythms - diurnal rhythms Somatoliberin (GHRH, growth hormone-releasing hormone) Characteristics - Two types present in hypothalamus - GHRH receptor (cAMP) - R – homology with R secretin, GLP-1, glucagon, calcitonin, PTH, PTHrP Hypothalamo-hypophyseal axis - Fast GH secretion - GHRH is not the only GR secretion modulator! - Synergy with estrogens, glucocorticoids and starvation - Somatostatin, age and obesity – decreased secretion Other functions and places of synthesis -Sleep regulation (SCN) -Orexigenic factor -Wound healing - skin -Ovaries, uterus -Placenta - Unknown role - Possible alternative splicing Clinical significance - Nowadays without clinical significance - GHRP Somatostatin (GHIH, growth hormone–inhibiting hormone ) Characteristics - SST-14 (CNS) and SST-28 (GIT) - Neurotransmitter – neuromodulator - SSTR1-SSTR5 (GP – cAMP – PLC, PLA, MAPK, ion channels) - diverse receptor distribution (mainly CNS) - SSTR5 – insulin secretion inhibition - SSTR2 – glucagon secretion inhibition Hypothalamo-hypophyseal axis - GH secretion regulation - TSH inhibition - PRL and ACTH secretion inhibition Other functions and places of synthesis - Myenteric plexus - Epithelial GIT cells - Endocrine pancreas – autocrine and paracrine - Cortex, lateral septum, amygdala, thalamic reticular nucleus - Hippocampus, brain stem nuclei - Cortistatin with SSTR1-5 affinity – neuromodulator (ant. Ach) - neurotransmitter - paracrine Clinical significance - Somatostatin analogues (octreotide, lanreotide, vapreotide, seglitide, pasireotide) - Therapy of acromegaly, TSH producing or neuroendocrine tumors - ! Negative GIT side effects - Imaging methods (111In-somatostatin) - Potential use in tumor treatment Main effects of somatostatin Inhibition of hormone secretion GIT inhibition Other Adenohypophysis – TSH, GH, ACTH, PRL Stomach and duodenal secretion including HCl Inhibition of activated immune cells GIT – gastrin, secretin, motilin, GLP-1, GIP, VIP Stomach emptying Inhibition of tumor growth (proliferation) Endocrine pancreas – insulin, glucagon, (somatostatin) Pancreatic enzymes and bicarbonates secretion Kidneys - renin Bile secretion Decrease of GIT blood flow Stimulation of intestinal water and electrolytes absorption - GHRH secretion stimulation - Ghrelin - Leptin - Galanin - GABA − a2-adrenergic and dopaminergic input - GRHR secretion inhibition - CRH − b2-adrenergic input - Somatostatin secretion inhibition - Ach - 5-HT-1D Somatoliberin, somatostatin – regulation of secretion Stimulation of GH secretion Physiological factors Hormones and neurotransmitters Pathological factors Exercise Arginin, lysin Acromegaly Stress (various causes) Neuropeptides (ghrelin, RHRH, galanin, opioids – m receptors, melatonin) TRH, GnRH Sleep Neurotransmitters (agonists a2-AR, antagonists b-AR, M1 agonists, 5-HTD1 agonists, H1 agonists) Glu, Arg Decrease in postprandial glycemia GABA IL-1, 2, 6 Starvation Dopamine (D2R) Protein depletion Insulin-induced hypoglycemia Estrogens Starvation, anorexia nervosa Testosterone Kidney failure Glucocorticoids (acute, not chronic) Liver cirrhosis DM 1st type Inhibition of GH secretion Physiological factors Hormones and neurotransmitters Pathological factors Postprandial hyperglycemia, glucosis infusion Somatostatin Acromegaly Increased FAA in plasma Calcitonin L-DOPA Increased GH concentration in plasma Neuropeptide Y D2R agonists Increased IGF-1 concentration in plasma CRH Phentolamin REM sleep Neurotransmitters (a1,2-AR antagonists, b-AR agonists, H1 antagonists, serotonin receptor antagonists, nicotine cholinergic receptor agonists) Galanin Aging Glucocorticoids (chronic) Obesity Hypothyroidismus Hyperthyroidismus Dopamine (PIH, prolactin-inhibiting hormone) Characteristics - D2R (G protein inhibition, AC, cAMP decrease, inhibition of shaker type K+ channels, MAPK, PAK – proliferation!) - D1R (activation) Hypothalamo-hypophyseal axis - Inhibition of PRL (D2R) secretion – lactotropic cells - ! Lactotrophs with continual high PRL production - PRL secretion regulated also on adenohypophysis level (paracrine, autocrine) - Neuroendocrine regulation of PRL secretion – pregnancy, lactation, menstrual cycle, sensoric inputs Other functions and places of synthesis - Blood vessels – vasodilatation (physiological concentrations) - Kidneys – sodium secretion - Endocrine pancreas – decrease in insulin secretion - GIT – lower motility - Effect of dompamine on immune system Clinical significance - Effect of medication on dopamine and PRL secretion - Cardial shock - Neurodegenerative diseases (Parkinson) - Antipsychotics (antag.) - Important feedback mechanism (short loop) of PRL secretion regulation - Circadian rhythm (maximum in the morning) - Nipple stimulation (1-3 min, peak 10 – 20 min) - Relevance of studying PRL secretion and its regulation - psychopharmaceutics! Dopamine – regulation of secretion PROLACTIN-RELEASING FACTORS (PRF) - TRH, oxytocin, VIP - under specific conditions ADH, ATII, NPY, galanin, substance P, GRP, neurotensin - prolactin-releasing peptide (PrRP) – stress, satiety (other parts of CNS) Enkephalin, dynorfin (m a k receptors) Gonadoliberin (GnRH, Gonadotropin-Releasing Hormone) Characteristics - Specific origin of GnRH neurons outside of CNS - GnRH-I, GnRH-II, (GnRH-III) – Gq/11 (PKC, MAPK) - Important up- and down- regulation (steroid hormones, gonadotropic hormones) - Downregulation – malnutrition, lactation, seasonal effects, aging, continual GnRH - Upregulation – effect of GnRH on gonadotrophs (menstrual cycle) - GNRH1 – hypothalamus; GNRH2 – other parts of CNS Hypothalamo-hypophyseal axis - FSH, LH - Importance of GnRH pulses frequency (glycosylation) - Menstrual cycle, puberty and its onset Other functions and places of synthesis - CNS – neurotransmitter (preoptic region) - Placenta - Gonads - Tumor tissue (prostate, endometrium) Clinical significance - Continually distributed analogues of GnRH – treatment of estrogen/steroiddependent tumors of reproductive system - Premature puberty treatment (leuprorelin – agonist!)- Unknown function - Inputs from various CNS regions (brain stem, limbic system) - Predominant inhibitory effect of sex-hormones with exception of estradiol (negative/positive feedback) - Importance of kisspeptin for females - Inhibitory effect of PRL - Effect of circulating substrates (FA, Glu) - Leptin (NPY, kisspeptin) - Stress (various causes) - Acute – disruption of MC without effect on fertility - Chronic – disruption of fertility, lowering of circulating sex-hormones levels Gonadoliberin – regulation of secretion Neurohypophysis Synthesis - magnocellular neurons (SON, PVN) Termination (neurohypophysis, eminentia mediana) Precursor protein (signal peptide, hormone, neurophysin 2, glycopeptide copeptin) Posttranslational modification – ADH/OT + neurophysins + copeptin Secretion – voltage-gated Ca2+ channels Circulation – free, elimination – kidneys, liver Neurophysins – importance – ADH transport and secretion Oxytocin Characteristics - Mechanoreceptors/tactile receptors - Magnocellular neurons (PVN, SON) - inhibition by endogenous opioids, NO, GABA - Autocrine (+ ZV) - Prolactin, relaxin (-), Estrogens (+) - OXT receptors (Gq/11) – effect of up/down regulation - Works together with prolactin and sex hormones Functions - Lactation (under 1 min) - Childbirth - rhythmical contractions of smooth muscles (gapjunction, stimulation of prostaglandin synthesis – extracellular matrix) - postpartum bleeding - uterus involution - Ejaculation (males) - Behavior Other functions and places of synthesis - CNS - Stimulation of ACTH secretion through CRH - Stimulation of ADH/induced vasoconstriction - Stimulation of prolactin secretion - Memory traces recollection inhibition - Maternal behavior Clinical significance - Oxytocin analogues OT receptors - OXT receptors (Gq/11) - Myoepithelial cells - Myometrium - Endometrium - CNS - PLC, IP3, Ca2+ - Target molecule – MLCK (myosin light chain kinase) Antidiuretic hormone (ADH, vasopresin, AVP) Characteristics - Magnocellular neurons (PVN, SON) - AVP receptors (G protein) - V1R - V1a (Gq/11) – liver, smooth muscles, CNS, adrenal glands – only ligand ADH - V2R (Gs) – kidneys - V3R - V1b (Gq/11) – corticotropic cells (CNS), kidneys, thymus, heart, lungs, pancreas, uterus Function - Water reabsorption (distal tubule, collecting tubule) – tubular system with different water permeability in different parts - AQP1 – proximal tubule, HL descending limb HK – 90 % of water reabsorption - AQP2 – collecting tubule (only ADH; acute X chronic effect) - AQP3, AQP4 - Vasoconstriction (hemorrhagic shock, sepsis) Other functions and places of synthesis - CNS – increased recollection of memory traces - Periphery – stimulation production of factor VIII and von Willebrand factor phosphorylation ADH - regulation of secretion - Osmotic regulation - Regulation volume-pressure - Predominantly inhibitory effect of R on magnocellular N ADH is the main hormone regulating water homeostasis and osmolality, RAAS is the main regulatory system of blood volume and pressure. ADH – osmotic regulation of secretion - Organum vasculosum laminae terminalis (OVLT) – „Osmostat“ - Insensitivity to urea and glucose - AQP2 - Acute effect (min.) - Chronic effect – circulating ADH (together with AQP3) – stays up to 24 hours plasma urine urine Thirst - Increase of plasma osmolality (2 – 3 %) - Lower IVF volume (over 10 %, usually 20 – 30 %) - Frontal region of hypothalamus – osmoreceptors - Low- and high-pressure baroreceptors - Together with ATII Max. 1.0 – 0,5 pg/ml Pregnancy – RESET OSMOSTAT - Decresed osmolality, increased IVF volume - from 5th – 8th week to 2nd week after birth - Vasodilatation - Effect of relaxin (+) and estrogens (+ NO) Old age – lower sensitivity to ADH, hypo-/hypernatremia Vasoconstrictive effect of ADH Ca2+.CaM MLCK activation Increased activity of myosin ATPase IP3 and mobilization of Ca2+ ADH – clinical aspects Diabetes insipidus (DI) - Primary polydipsia - Decreased ADH synthesis/secretion (ADH gene) (neurogenic) - Decreased kidney sensitivity (nephrogenic) SIADH – Syndrome of Inappropriate Antidiuretic Hormone Secretion - Increased ADH synthesis/secretion - Absence of physiological ADH secretion stimuli Absence of thirst after osmotic stimulation Ethanol lowers ADH secretion Unregulated ADH secretion Increased basal ADH secretion Reset of osmostat Decreased ADH secretion Adenohypophysis HORMONE PRODUCTION UNDER DIRECT HYPOTHALAMIC CONTROL - ACTH – adrenocorticotropic hormone - TSH – thyreotropic hormone - GH – growth (somatotropic) hormone - PRL – prolactin - LH – luteinizing hormone - FSH – follicle-stimulating hormone Adenohypophyseal cells Represent ation Hypothalamic hormone(s) Adenohypophyseal hormones Localization Lactotropic Up to 25 % Dopamine prolactin whole AH Cortikotropic Ca 20 % CRH POMC – ACTH, bLPH, a-MSH, b-end. Anteromedial region Thyreotropic Ca 5 % TRH TSH Anteromedial region Gonadotropic Up to 15 % GnRH LH/FSH Posterolateral region Somatotropic Ca 40 % GHRH/GHIH GH Posterolateral region Adenohypophyseal hormones Nerveendings–eminentiamediana neurohormones +/- Receptor(Gprot.) Suprachiasmatic nucleus Circulating hormones Feedback system Circadian rhythms Sleep (dwaves Sleep–TSH (st.1st,2ndNREM) Physiologicaleffect–homeostasismaintainance Adenohypophyseal hormones G protein-coupled receptors JAK/STAT signaling Glycoproteins - TSH Characteristics - Heterodimer − b subunit – transcriptional factors GATA2 and Pit1 - Negative feedback T3 – inhibition of a subunit transcription; dopamine (a and b) - Positive feedback – TRH - Co-translational glycosylation and folding (- T3, + TRH) Function - Stimulation of thyroid hormones synthesis - Growth hormone for thyroid gland Secretion regulation - 2-3 h pulse + tonic non-pulsatile secretion - Peak between 23:00 and 5:00 - Stable for 24 hrs. Secretion without other factors (gender, BMI, etc) - TRH (paracrine), transporters OATP and MCT - T3 – deiodinases 2 (+T3) and 3 (-T3) with different expression - Catecholamines – increased of setpoint for TRH inhibition - Somatostatin (-), glucocorticoids (-), NSA (-) - Dopamine (-) Clinical significance - TSH deficiency (mutation in genes coding TRH and TSH receptors) - Analogues of somatostatin - ! (+) cortisol metabolism Glycoproteins – FSH a LH Characteristics - Heterodimer, different expression of subunits, glycosylation - Structurally close to hCG (placenta) Regulation of secretion - sex hormones, local factors – paracrine (activins, inhibins, follistatin) - (+) – glutamate, noradrenaline, leptin - (-) – GABA, opioids - Key role of kisspeptins, neurokinin B and substance P in GnRH secretion – FSH/LH - Estrogens, progesterone, androgens – direct influence on gonadotrophs, indirect influence through GnRH - Estrogens (-) – inhibition of transcription (a), kisspeptin – NEG - Estrogens (+) shift - Progesterone (-) – influences pulsatile secretion of GnRH - Testosterone, estradiol (-) – males, kisspeptin neurons and AR - GnRHR – Ca2+ mobilization - Different half-life for circulating LH and FSH Activins and inhibins Inhibins – dimeric peptides (a + 1 or two bA or bB) – circulating hormones produced by gonads – inhibin A – dominant follicle, corpus luteum – inhibin B – testes, luteal and early follicular phase of MC Activins – dimeric peptides – dimers of b subunits –FSH stimulation – autocrine/paracrine factors – other tissues – growth and differentiation Folllistatin – monomeric polypeptide – FSH inhibition - „supplementary “ regulation of FSH and LH secretion - activins = regulation of transcription, follistatin and inhibins = inhibition of activins through appropriate activin-receptor binding FSH and LH functions FEMALES - FSH - Growth and development of follicular cell (maturation) - Biosynthesis of estradiol - Regulation of inhibin synthesis during follicular phase - Upregulation of LH receptors (preovulatory follicles) - Selection of dominant follicle - Recruitment of follicles for next cycle - LH - Stimulation of estrogen synthesis on various levels (theca) - Oocyte maturation (preovulatory follicle) - Rupture of ovulatory follicle, ovulation - Conversion of follicle wall to corpus luteum Clinical significance - Possible deficiency of gonadotropins - Hypogonadotropic hypogonadism - Kallmann syndrome - Syndrome Prader-Willi - Reproductive dysfunction MALES - LH - Intratesticular synthesis of testosterone (Leydig cells) - FSH - Spermatogenesis (Sertoli cells) Proopiomelanocortin - POMC Characteristics -Adenohypophysis - short transcript -CNS -Placenta -Skin -Gonads -GIT -Liver -Kidneys -Adrenal medulla -Lungs -Lymphocytes Stimulation of expression -CRH, cytokines, ADH, catecholamines, VIP Posttranslational modification - Role of prohormone convertases (PCs) long transcript with synthesis of products regulating energetic metabolism Functions of POMC-derived peptides Adrenal glands - ACTH - the only POMC hormone with effect on adrenal glands - MC2R receptor for melanocortin) - Glucocorticoids, androgens, (mineralocorticoids) - Mitogennic effect on adrenal glands (N terminal peptide) Skin pigmentation – ACTH, b-LPH, g-LPH - MC1R - Paracrine regulation (melanocytes, keratinocytes) Regulation of appetite – a-MSH - Inhibition of inhibitory effect of leptin - Activation of MC3R and MC4R (hypothalamus) Immune functions – a-MSH - Inhibition of leukocyte migration - Inhibition of macrophage functions - Modulation of antigen-presenting and T cells Analgesia – b-endorphin - Circulating probably without effect on CNS Placental POMC - 2nd trimester - Decrease 3 days after birth - No correlation to ACTH/cortisol of mother - Unknown physiological function Ectopic synthesis of POMC/ACTH - Mainly tumors with ability of posttranslational changes ACTH Secretion -Circadian and ultradian rhythms -Rise from 16:00 with peak before 19:00 -Lowest levels between 23:00 and 3:00 -pulsatile secretion (ca 40/day, higher in males) ACTH and stress - Complex – peripherial and central stress adaptors - Vasovagal and sympathetic activation (catecholamines), cytokine secretion - Pain, infection, inflammation, bleeding, hypovolemia, trauma, hypoglycemia, psychological stress - Higher amplitude of ACTH pluses Secretion regulation - Very complex - neuroendocrine control of stress response and homeostasis - Regulatory molecules – CNS, hypothalamus (CRH, ADH, dopamine) – corticotropic cells - Cytokines (IL-6, LIF), growth factors – adenohypophysis – local control (paracrine) - Glucocorticoids - Negative feedback mechanism – inhibition of CRH secretion, decrease of basal ACTH secretion - Modulation of somatostatin inhibitory effect (downregulation of R) - Dopamine - Physiological regulation of secretion – exercise (athletes – hypercortisolism) Function - Adrenal glands size, structure and function - Steroidogenesis stimulation Clinical significance - Deficiency ACTH - Hypersecretion of ACTH - Testing - insulin Prolactin - PRL Characteristics - Lactotropic cells (only PRL) - Mammosomatotropic cells (PRL and GH) - Hyperplasia – pregnancy and lactation - Expression regulated by estrogens, dopamine, TRH, thyroid hormones - Polypeptide circulating in three forms (mono-, di-, polymer) - Monomeric PRL with highest biological activity - Monomeric prolactin further spliced (8/16 kDA) - 16 kDA PRL – antiangiogenic function - PRLR – mammary gl., adenohypophysis, adrenal gl., liver, prostate, ovaries, testicles, small intestine, lungs, myocardium, SNS, lymphocytes Regulation of secretion - pulsatile secretion – 4 – 14 pulses/day - Highest levels during sleep (REM, nonREM) - Lowest between 10:00 and 12:00 - Lower secretion with aging - TIDA cells – dopamine (-, D2R) - Paracrine – endothelin-1, TGF-b1, calcitonin, histamine (-) - FGF, EGF (+) - TRH, estrogens, VIP, serotonin, GHRH in higher concentrations (+) - Cholecystokinin - ? Prolactin - functions Production of breast milk during pregnancy and lactation = function necessary for survival Other functions – metabolic, melanin synthesis, maternal behavior Development of mammary gland and lactation - Puberty – development of mammary gland due to GH and IGF-1 - Effect of estrogens and progesterone - At age 8 – 13 - During pregnancy proliferation of alveoli and production of breast milk proteins and colostrum - During third trimester – colostrum production (PRL, estrogens, progesterone, GH, IGF-1, placental hormones) - Lactation – increase of PRL after birth, without breastfeeding decrease after ca 7 days - Accumulation of breast milk stops further production - Role of OT Reproductive function of PRL - Lactation = amenorrhea and secondary infertility - Inhibition of GnRH secretion - Role of kisspeptin neurons (PRLR) - Possible role of metabolic factors Immune function of PRL - Antiinflammatory effect ? Clinical significance - hyperprolactinemia – drugs including some antihypertensives, chronic kidney failure - Macroprolactinemia - Galactorrhea – role of GH (acromegaly) - PRL deficiency Growth hormone (GH) Characteristics -hGH genome – 5 products including human chorionic somatomammotropin -hGH-N – somatotrophs – 20/22 kDA -hGH-V – placenta – feedback regulation -Circulating GH: - 20 (25 %) and 22 kDA (75 %) monomers - Acetylated 22 kDA form - Deaminated forms Regulation of secretion -GHRH, somatostatin, ghrelin, IGH-1, thyroid hormones, glucocorticoids -Relatively complicated system of regulation: - Neuropeptides - Neurotransmitters - Endogenic opioids Growth hormone (GH) – regulation of secretion - GHRH (continual), somatostatin (pulsatile secretion) - Desensitization of R for GHRH - IGF-1 - somatostatin - Ghrelin - GHS receptors – stimulation of GHRH secretion - Synthesis – stomach and CNS, regulation of food intake - Diurnal rhythm with maximum during sleep (first episode of slow-wave sleep) - Very low basal secretion, decrease with age (peak in puberty, then decrease) Growth hormone (GH) – regulation of secretion - „jet lag“ - exercise - physical stress including infection, sepsis - Malnutrition (+) - Obesity (-) - Glucose (-) - Arginine, leucine (+) - FFA (-) - leptin GH and interaction with other hormanal axes ACTH – Glucocorticoids - Acute (+) – effect after ca 3 hours - Chronic (-) TRH – TSH – thyroid hormones - Necessary for GH secretion - Hypothyroidismus (-) GnRH – FSH a LH – sex hormones - Testosterone (+) - Estrogens (+) – only p.o. – decreased inhibition of IGF-1 + feedback - aromatization of androgens affects GH synthesis and secretion (paracrine effect of estrogens in CNS) TRANSPORT -GHBPs -20 kDA with low affinity -60 kDa with high affinity -Obesity (+) -Pregnancy (+) -p.o. estrogens (+) -Malnutrition (-) -Cirrhosis (-) -Hypothyroidism (-) -Androgens (-) -Glucocorticoids (-) GH – receptors and cell signaling - GHR (dimer) - JAK-STAT - Liver - Adipose tissue - Skeletal muscles - Mutual integration of signaling pathways? GH and its effects METABOLIC -Energetic metabolism -Together with insulin (metabolism of sugars, fats, proteins) -Lipolysis and FA oxidation(+) (hormone-sensitive lipase, + LDL) -Glucose – direct or indirect effect, - (+) uptake of Glu - (-) Glu oxidation - (+) gluconeogenesis -Proteins - (+) anabolism, (-) urea - (+) AA transport - (+) incorporation of AA to proteins - (-) protein oxidation GROWTH -Mediated by IGF-1 (auto-/paracrine) GH – clinical aspects GH deficiency – gained or congenital – often tumors or inflammation - nonspecific symptoms (i.e. loss of energy, social isolation, loss of focus) - myocardium changes (left ventricle) GHR – mutation Significance of markers (IGF-1, IGFBP3) Substitution therapy – wide array of side-effects, contraindication – cancer Experimental indications: - catabolic states (i.e. extensive burns) - osteoporosis - HIV/AIDS - sport medicine - aging MSH – melanotropins α-MSH: Ac-Ser-Tyr-Ser-Met-Glu-His-Phe-Arg-Trp-Gly-Lys-Pro-Val β-MSH: Ala-Glu-Lys-Lys-Asp-Glu-Gly-Pro-Tyr-Arg-Met-Glu-His-Phe-Arg-Trp-Gly-Ser-Pro-Pro-Lys- Asp γ-MSH: Tyr-Val-Met-Gly-His-Phe-Arg-Trp-Asp-Arg-Phe-Gly - Pregnancy (+) - Adrenal glands (hypofunction) Clinical significance -Synthetic analogues -Afamelanotide – photoprotection -Melanotan II – increased libido -Bremelanotide – aphrodisiac effect (MC3R and MC4R)