MT 6 - Endocrinology Flashcards
- Classification of hormones, the dynamics of the receptor ligand interaction, the feedback mechanism:
Classification of hormones
- Lipid-soluble - E.g. steroid
- Lipophilic-easily pass plasma membr. and act IC
- Carrier proteins->long half-life in plasma
- Directly act on nucleus
- IC mediator: receptor-hormone complex
* passes nuclear envelope and stim/inhib gene expression - Lipid-insoluble - E.g. catecholamines
- Hydrophilic-exert their effects on surface receptors
- Normally no carrier proteins->short half-file
- IC signaling mediated by IC “secondmessengers”
- Classification of hormones, the dynamics of the receptor ligand interaction, the feedback mechanism:
Dynamics of the ligand-receptor mechanism
•In vitro:
-Interaction bw. hormone and receptor is governed by physicochemical laws
-Scatchard analysis: characterized the dynamics of binding reactions bw. small molecules and proteins.
•His theory can be applied to any biological system, where a substance (ligand) binds to a large-molecular binding site (receptor).
•The stronger the ligand-receptor connection is, the more non-labeled hormone is required to displace the radioactive hormone from the receptor.
•Two characteristic values:
1. Bmax: number of the total binding sites.
2. Kd: dissociation constant of the binding site
•In vivo:
-We introduce a radio-labeled hormone into the circulation and examine the dynamics of the appearance, staying, and removal of this hormone in organs as a function of time.
- Classification of hormones, the dynamics of the receptor ligand interaction, the feedback mechanism:
The feedback mechanism
•When the central facilitation is inhib. by the incr. prod. of hormones, the hormone production will be inhib. by the conc. of hormones in the system.
•Low conc. of hormones will elicit prod., while high conc. will inhibit prod.
•Long, short and ultra-short feedback:
-Long feedback: from periphery to hypothalamus
-Short feedback: from periphery to pituitary gland
-Ultra-short feedback: bw. hypothalamus and pituitary gland
- Communication among cells, intracellular receptor signaling: Communication among cells
- Hypothalamus: most important organ in cell signalling regulation; because of its central integrating role.
- Intracellular communication:
1. Direct comm.: Transp. substances via gap junctions. - Ionic transp. bw. cytoplasm of one cell to another (requires cells to be close)
2. Contact comm.: Info. processing by molecules integrated in cell memb. - Typical method in immune system (requires cells to be close).
3. Comm. by secretion: Secr. molecules bw. cells that are not so close. - Important for function of immune and nervous system.
- Secretion can be endocrine, paracrine, autocrine or neurotransmitted secretion.
4. Cytoskeletal comm.: Processing mechanical info. that will influence the cell by cytoskeletal system
- Communication among cells, intracellular receptor signaling: type of communicating secretion
- Endocrine secretion: specialized cells will secrete hormones that will reach the recipient cells through the bloodstream.
- Paracrine secretion: bw nearby cells, local chem. mediators will be broken down, immobilized or taken up by cells close to the producer - very quickly
- Autocrine secretion: when the cells own signal will affect it. A type of paracrine effect.
- Neurotransmitted secretion: a synaptic transmission causes the cells to secrete neurotransmitters. Can be found in the CNS and in ANS
- Communication among cells, intracellular receptor signaling: intracellular receptor signaling
- Lipophilic hormones can pass the cellular membrane and bind to cytoplasmic receptors
- Then they reach the nucleus and exert the effect.
- The receptor–ligand complex is able to enter the nucleus, and the DNA-binding domain of receptor “finds” DNA segments, called HRE`s.
- Then it activates the structure gene downstream to HRE and a biological response is initiated trough a protein(enzyme)
- Membrane receptor signalling
-Receptor: may be a special transmembrane protein of 3 parts:
1.Ligand binding part (on EC side)
2.Central part (passes through membrane)
3.Inner part (on IC side)
-Nicotinic Acetylcholine Receptor:
•Ion-channel forming a transmembrane protein
•Found in CNS & PNS
•In closed state before binding of ACh
*Binding of ACh->conformational changes->opening of cation channel
*Influx of cations->local excitatory pot. & stim. of AP
*Channel returns to closed state after dissociation of ligand
-Glutamate-sensitive receptors:
•Post-synaptic membrane-integrated cation channels
•3 main groups according to glutamate antagonists
1.NMDA receptor (N-metyl-D-aspartate)
*Binding of Mg2+->receptor closed
*Mg2+ dissociation->receptor activated
2.AMPA receptor
3.Kainate receptor
-Anion Receptors:
•Opening of anion channels, important in inhibitory synapses of CNS
•2 main mediators:
1. GABA: acts on GABA-A (ionotropic) or GABA-B (metabotropic) receptors.
2.GABA-B decreases IC cAMP & effects K+ channels.
- Hypothalamic releasing and inhibiting factors: Hypothalamus
•The highest cerebral integrator of autonomic functions, and it synchronizes neural and hormonal activity.
•Hormones in parvocellular area go to adenohypophysis
-Consist of supraoptic nucleus and paraventricular nucleus
-Secrete oxytocin, vasopressin, TRH, CRH and neurotensin
-The neurosecretion go down the axon, reach portal circ. of pituitary stalk of median eminence and then reaches anterior lobe of pituitary gland.
-Releases hormones into the vascular system.
•Hormones in magnocellular area go to neurohypophysis
-Consist of ventromedial, dorsomedial and infundibular nucleus
-Contains liberin or statin
-Secrete oxytocin-prod. cells and vasopressin-prod. cells
-The neurosecretion goes down inside axon from site of prod. to site of release.
- Hypothalamic releasing and inhibiting factors
•Hypophysotropic: h. prod. in hypothalamus
•TRH: thyrotropin releasing h. Stim. thyroid gland h.
•CRF: corticotropin releasing f. Adrenocorticotropin stim. hormone. Facilitates synt. of ACTH, MSH and opiates, also splitting POMC.
•GnRH: gonadotropin releasing h. Facilitates synt. of FSH and LH.
•GRF: growth h. releasing f.
•GIH: growth h. inhib. h.
•PRF: prolactin releasing f. Responsible for lactation, and ovulation in rat.
•MRF: melanocyte releasing f. Activator of MSH. Inhib. factors are dopamine, somatostatin, GABA and VIP.
•PIF: Prolactine inhib. f. (dopamine)
•VIP: Vasopressing inhib. protein. Incr. synt. and secr. of prolactine and other anterior pituitary h. Acts neg. on synt. of somatostatin
-Angiotensine 2: a sep. h. in hypothalamus, but also prod. in periphery.
•Acts on hypothalamus and pituitary gland. Stim. synt. and release of somatotropin and prolactin.
- Adenohypophysis, the synthesis and release of ACTH: Adenohypophysis
-Anterior lobe of hypophysis •Endocrine gland found in Rathke’s pouch -Developed from entodermal glandular tissue during embryonic life. •Hormones: -TSH, ACTH, FSH and LH: act only on endocrine glands - are glandotropic. -PRL and STH: are histotropic *TSH: thyroid stimulating hormone *ACTH: adrenocorticotropic hormone *FSH: follicle stimulating hormone *LH: luteinising hormone *PRL: prolactin *STH: growth hormone (somatotropin)
- Adenohypophysis, the synthesis and release of ACTH: Synthesis and release of ACTH
•The brown area (central part) of adenohypophysis prod. ACTH.
•Derived from Pre-POMC, and is therefore involved in the adaptive processes of the organism.
•ACTH helps to mobilize energy reserves and decr. pain sensation during stress.
-Regulated by feedback principle; long and ultra-short
•Long: incr. glucocorticoid conc. Glucocorticoid prod. is stim. by ACTH, and will elicit at neg. feedback on ACTH synt.
•Ultra-short: ACTH inhib. CRF. Neural impulses reaching hypothalamus are integrated by CRF synt. cells. The release of CRF is pulsatile and its circadian fluctuation determines synt. and secr. of ACTH.
- Growth hormone: general about growth hormones
•Normal growth maintained by continuously high levels of STH (somatotropin), and pulsatile incr. and decr. of STH.
•STH: prod. in acidophil cells of adenohypophysis.
-Both short and long duration fluctuation.
-Synt. by effect of GRH and GIF
•Gigantism: Incr. secr. during young age
•Acromegaly: Incr. secr. during adult life, bone growth and asymmetrical growth of limbs
•Dwarfism: Decr. secr. during young life
- Growth hormone: Effects and regulation
-Effects on protein metabolism: STH incr. uptake of aa. in cells -> incr. IC protein synt. -> incr. growth
•Directly stim. by free aa. in plasma
-Effects on lipid metabolism: start lipolysis -> stim. GNG.
•High STH conc: stim. conversion of FA into acetic a.
• = STH mobilises E stores to cover E needs of protein synt.
-Effects on carbohydrate metabolism: STH inhibit insulin-facilitated glu uptake in adipose tissue -> incr. plasma glu level -> incr GNG
•STH also stim. prod- of glucagon.
*Too much STH: pathological hyperglycemia, because STH have an antiinsuline-like and glucagon agonist effect.
-Indirect effects of STH:
•IGF (insulin-like growth factors) influence bone, cartilage and CT: stim. bone formation, bone growth and acromegaly in adults
-Regulation of STH secretion:
•Low glu level and decr. level of arginine in plasma will stim. STH secr.
•Synt. and release will be stim/inhib by plasma hypothalamic factors according to the actual needs. These adjustments will be done by endogenous hypothalamic signals.
- Hormones from the neurohypophysis: Neurohypophysis
•Posterior lobe of hypophysis - extension of hypothalamus
- Developed from ectodermal nervous tissue during embryonic life.
- Oxytocin and vasopressin: hormones prod. in hypothalamus, but stored and secr. from neurohypophysis.
- Hormones from the neurohypophysis
-Oxytocin:
•Stim. uterus, especially during late pregnancy and birth.
•During birth oxytocin helps keep the strength of labour contractions.
•You can give oxytocin to “activate” labour.
•The prod. of oxytocin will also be stim. by breastfeeding of the baby.
-Vasopressin:
•Functions on kidneys, helps regulate the loss of water by regulating uptake of water from urine. This will also help reduce the level of urine.
•Dehydration will be very stim. for vasopressin, because of the huge need for water abs. and storage.
•If the vasopressin secr. were to be inhib., the amount of urine would be doubled almost 10 times.
- MSH and the Pinneal gland: MSH
•Melanocyte stim. hormones
•Mostly known effect of this hormone family is stim. of pigment granule prod. and transp. along the microtubule system in pigment cells: resulting in the decoloration of cells
-Alpha MSH: formed from ACTH
-Beta MSH: formed by beta lipotropin
-Gamma MSH: cleaved from N-terminal of POMC.
-Effect of MSH on pigment cells:
•From nucleus of pigment cells to periphery there is a microtubule system arranged in a radial symmetry. In resting state, pigment granules are located around nucleus.
•MSH exerts migration of pigment granules along the microtubule matrix system, which is a process connected to activation of motoproteins.
•The pigment is evenly distributed in the cell, and the cell or tissue becomes darkened.
•MSH also facilitates pigment synthesis.
- MSH and the Pinneal gland: Pinneal gland
•Located caudo-dorsally from hypothalamus and composed of pinealocytes and glial cells. •Synt. serotonin and melatonin -Melatonin prod. has a circadian rhythm which depends on light exposure; darkness acts pos, while strong illumination (daytime) acts neg -Serotonin prod. starts in light -First step of melatonin synt. is transformation of serotonin to N-acetylserotonin by NAT -Function of melatonin: •Skin: opposite to MSH: induces conc. of pigment granules -> skin becomes pale •In mammals, 3 important effects: 1.Sexual function -inhib. sexual maturation (humans) -inhib. GnRH-FSH-LH axis -human ovulation -incr. sexual cycle in cat and horse -decr. sexual cycle in sheep and goat 2.Psychic effects -incr. depression, appetite, sleepiness -jet lag 3.Defence against free radicals
- The thyroid hormones: The thyroid
•Develops during early embryonic life; because thyroid hormones can´t get through the placenta.
•Prod. metabolites into the bloodstream and iodine containing hormones.
•Hormones: thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3) and calcitonin.
-Important for metamorphosis-normal development, reg. of intermediary metabolism and homeothermy-stabile thermogenesis.
*Facilitate carb. metabolism, incr. lipid metabolism and stim. protein metabolism.
*Also have a neuronal and a cardiovascular effect
*Calcitonin has an effect on bone metabolism
-Defects:
1.Hypothyroidism: deficiency of thyroid h.
*Young: dwarfism and slow sexual development.
*Adult: loss of hair/fur, slow reflexes, low/none reproductive abilities
2.Hyperthyroidism: overproduction of thyroid h. Same effects in adult and young; incr. BMR and O2 consumption, weight loss and incr. irritability.
3.Goiter: Enlargement of thyroid gland, also called struma. Often occurs at the same time as hyper or hypothyroidism.
- The thyroid hormones: Synthesis
-Thyroglobulin will be degr. by follicular cells to hormones (T4, T3 and rT3)->ready for entering circ. Every step but the release is facilitated by TSH hormone.
Steps:
1.Iodine enters the gland by active pumps
2.By the help of lysosomal peroxidase enzyme the iodine will be converted into atomic iodine.
3.The atomic iodine makes monoiodotyrosine (MIT) consisting of 1iodine or diiodotyrosine (DIT) consisting of 2iodine. The MIT or DIT will then bind to TG. 2DIT will make one T4, while 1DIT + 1MIT will make either one T3 or rT3.
4.Epithelial cells synt. colloid TG, for the purpose of storing hormones.
5.Endocytosis of TG will be the first step of hormone release
6.Only T4 and T3 get into bloodstream, while other proteins will be degr. IC.
7. T4 and T3 will be secr. at basal side of cells by help of passive diffusion.
- The thyroid hormones: Regulation
- Controlled by feedback regulation, both long and short.
- Long feedback is under the effect of TRH synt, while short is under effect of TSH synt. Both long and short feedback reg. are inhib. by T3.
- T3 is mostly derived from T4 (T4 becomes T3 in the tissue).
- T4 is reg. by exogenous and endogenous factors.
- Exogenous factors: photoperiod, feeding, temp., stress and pharmacons (drugs).
- Endogenous factors: genetic determination, physiological state, changes of hormone receptors and tacivation ability of peripheral cells.
- Synthesis, regulation and physiological effects of glucocorticoids: Glucocorticoids
•Prod. in adrenal cortex, and belongs to steroids.
•3 zones of adrenal cortex:
1. Zona glomerulosa/zona arcuata
2. Zona fasciculata
3. Zona reticularis
•Glucocorticoids are prod. in zona fasciculata, but also some prod. in zona reticularis.
•Most important glucocorticoids: Cortisol and corticosterone
-Rat, rabbit and pigeon: corticosterone dom.
-Cattle and dog: the hormones occur in equal conc..
-Sheep, pig and human: cortisol is important
- Synthesis, regulation and physiological effects of glucocorticoids: Regulation
- Hypothalamic–pituitary (CRF – ACTH) control is the basis of reg.
- Prod. in zona reticularis is less dependent on ACTH.
- The roles of glucocorticoids are determined by long feedback loop.
- Synthesis, regulation and physiological effects of glucocorticoids: Physiological effects
•Long lasting mobilization of energy reserves of the body.
•Metabolism:
-carbohydrate metabolism: hyperglycemia
-protein metabolism: protein catabolism
-lipid metabolism: cleaving of fats, redistribution
•Other physio. effects: Circulatory, blood cell, lymphoid, nervous system
-Defects: Glucocorticoid insufficiency: Na+ loss, oligemia, K+ increase (cardiac weakness), edema in capillaries, muscular weakness.
- Pharmacological effect of glucocorticoids
•Utilized in veterinary practice because of their excessive antiinflammatory effect.
•Effects of continuous high level of glucocorticoids: on mesenchymal cells, Antiphlogistic effect and Antiallergic effect
-Effect on medenchymal cells:
•Inhib. of proliferation of mesenchymal cells:
*Fibroblast and collagen formation is inhib., cicatrisation is considerably prolonged.
*Normal granulation and total healing of wounds are inhib.
*Osteolysis is remarkable: osseous matrix is degr., Ca is mobilized and excreted and, in the end, osteoporosis develops.
-Antifphlogiatic (anti-inflam) effect:
•Due to the phospholipase A2 blocking effect of glucocorticoids
*decr. inflam. color, dolor and tumor
*decr. basophil degranulation (decr. allergic reactions)
*Masking effect: since corticoid treatment only decreases inflam. symptoms, it is not meant to be a causal treatment
-Antiallergenic effect:
•Significantly inhib. histamine release
•Do not have a direct influence on Ag-AB reaction
