Download - Endocrine System Physiology
ENDOCRINE SYSTEM PHYSIOLOGY
Definition of a hormone• Hormone is any substance used by cells to exchange information
via circulatory system• Hormone is released to the bloodstream by information-sending
cells• Hormone acts on specific receptors located in information-receiving
cells• Response of target cells to a hormone depends on the expression
of: - receptors themselves - receptor downstream effectors concerning signal transduction - downstream effectors of proteins regulated during the signal
transduction, determined by what we generally call „cellular differentiation”
Signal transduction
• Means converting the intercellular signal conveyed by a hormone to intracellular signal within the target cells
• Comprises a set of proteins, including: - hormone receptor - second messengers - downstream effectors for second
messengers (protein kinases, ion channels, etc.)
Classification of hormones, according to their chemical structure:
• Peptides (e.g. insulin, ADH, PTH, leptin)• Aminoacid derivatives: - hydrophilic derivatives (e.g. adrenaline,
noradrenaline) - lipophilic derivatives (thyroid hormones:
thyroxin and triiodothyronin)• Steroids (e.g. sex hormones, aldosterone,
cortisol)
Classification of hormones, according to their receptor structure and function:
• Hormones acting through G protein coupled receptors (GPCRs) – e.g. almost all peptides, excluding ANP, insulin, IGFs and leptin
• Hormones acting through catalytic receptors, activating second messenger production without G proteins (ANP)
• Hormones acting through thyrosine kinase coupled receptors (insulin, IGFs, leptin)
• Hormones acting through intracellular receptors (lipophilic hormones crossing cell membranes – e.g. steroids, iodothyronines)
GPCRs – G protein coupled receptors
• Are cell membrane proteins• When stimulated by a hormone (their ligand)
they activate G proteins (using GTP as an energy source for activation)
• G proteins may be stimulatory (Gs) or inhibitory (Gi)
• Target enzymes for G proteins most often include: adenylyl cyclase or phospholipase C
Acting through GPCRs as a classic example of signal transduction
• „Transducts” the hormone-mediated signal through the cell membrane (hormones acting through GPCRs usually cannot cross cell membranes by simple diffusion)
• Influence of a given GPCR stimulation on second messenger synthesis depends on whether it is coupled with Gs or Gi protein
• Altogether effect of activation of this system (receptor – G protein – target enzyme for a given G protein) depends on the kind of the enzyme (adenylyl cyclase, phospholipase C, etc.) and direction of action executed by G protein (stimulation or inhibition)
Selectivity and specificity of GPCR-acting hormones, as well as their actions, are determined by:
• Receptor expression (only in target cells)• Receptor specificity (selective affinity only to a
given hormone)• Receptor arrangement (type of G protein it is
coupled with, and a type of target enzyme for that G protein)
• Cellular differentiation of a target cell (because it determines the exact pattern of expression of downstream effectors for second messengers)
Second messengers and their actions
• cAMP activates protein kinase A (PKA)• Diacyloglycerol (DAG) activates protein kinase C or, in
some cells, protein kinase B• Inositol triphosphate (IP3) activates calcium channels in
endoplasmic reticulum• Calcium ions entering the cytoplasm form a complex with
calcium-binding regulatory proteins (e.g. calmodulin, calbindin, calcineurin) and subsequently their downstream kinases (calcium-activated kinases) or other calcium-dependent intracellular processes (e.g. contraction of muscle cells)
Target substrates for protein kinases (A,B, or C) determine the pattern of final physiological effects of GPCR-acting hormones in
their target cells
• Action of protein kinases comprises regulatory PTMs of many intracellular proteins (from metabolic enzymes to transcription factors)
• The exact pattern of physiological response of a given type of cells to a given hormone may depend on cellular differentiation
• Examples: TSH and NISP in thyroid glandular cells (Gs – cAMP); TSH and thyroid size (Gs – PLC products)
Thyrosine kinase coupled receptors
• Provide signal transduction for some peptide hormones (e.g. insulin, IGFs, leptin)
• Receptor activation directly activates thyrosine kinase (i.e. enzyme that phosphorylates thyrosine residues within its target proteins)
• Action of this kind of receptors is generally mitogenic and upregulating protein synthesis
• Intermediate downstream effectors of thyrosine kinase coupled receptors (c-JUN, c-RAS, etc.) include many protooncogenes (i.e. proteins that may contribute to uncontrolled mitosis when they „go awry” – e.g. as a result of gain-of-function mutation)
Cytoplasmic intracellular receptors
• Account for physiological effects of steroid hormones
• Have a hormone-binding domain (selective for a given hormone) and a DNA-binding domain
• Whereas hormone-binding domain is selective for a given hormone, DNA-binding domain is selective for a specific sites in the genome
• Receptor-specific sites in the genome are called „hormone response elements” (HRE)
Nuclear intracellular receptors
• Are constantly bound to specific regions of DNA as non-histone proteins
• They simply „turn on” upon hormone stimulation
• They provide mechanisms of action for thyroid hormones and retinoids
• They directly regulate gene expression at the level of transcription
HORMONE SYNTHESIS, TRANSPORT, AND CLEARANCE
Peptide hormones
• Are initially synthesized as inactive precursors (pre-prohormones)
• They undergo a two-stage posttranslatory processing (PTP)
• First stage of PTP (occurring in ER) can be aimed at a proper conformation of the final hormone
• Second stage of PTP (occurring in Golgi apparatus) comprises final activation and packing the hormones into secretory granules, or storage vesicles
• Peptide hormones are stored by the producing cells, so they can be synthesized much before secretion
Remainings of PTP (secretagogues)
• Include peptide chains excised from a prohormone during PTP
• Example: C peptide and insulin• They are often secreted by hormone-producing cells in
amounts equimolar to the related hormone• Therefore; assessment of their concentration in the
blood can be used for evaluation of endogenous hormone secretion, even when a patient receives hormone replacement therapy (e.g. evaluation of pancreatic islet function in diabetics treated with insulin)
Steroid hormones
• Can cross phospholipid membranes, so they cannot be stored in „storage vesicles”
• However, enzymes necessary for their synthesis can be stored, and thus can be synthesized much before hormone production
• Stimulation of steroid hormone production means stimulation of their secretion
Hormone transport in the bloodstream
• Does not require any carrier proteins for hydrophilic hormones (peptides, amines)
• Requires carrier proteins for steroid and thyroid hormones• Carrier proteins improve hormone solubility in the plasma• Carrier proteins prevent rapid uptake of hormones by the
cells proximal to their site of synthesis; thus providing homogenous distribution of the hormones through the whole organism
• Carrier proteins prevent rapid hormone degradation, so they usually extend their half-elimination time
• Carrier-bound fraction of a hormone may be used as a „reserve pool” in case of a transient deficiency of substrates necessary for the hormone synthesis
Carrier proteins for hormones
• TBG (thyroxin binding globulin)• TBPA (thyroxin binding prealbumin; also called
transthyretin)• CBG (cortisol binding protein; binds also
aldosterone; referred to as transcortin)• SHBG (sex hormone binding globulin) – binds
gonadal hormones, gestational hormones and adrenal androgens
Methods used to „uncouple” hormone secretion from their synthesis
• Synthesis takes some time, while secretion should be fairly quick to provide effective regulation
• Peptide hormones and amines are stored in „storage vesicles” or secretory granules
• Steroid hormones are not stored, but the enzymes allowing quick synthesis when necessary – can be stored by steroid-producing cells
• Thyroid hormones are sequestrated in non-vascularized extracellular environment (inside of thyroid glandular follicles) and protected from „leakage” by covalent binding to thyreoglobulin
Elimination, or „clearance” of hormones from the blood
• May occur through the uptake by the target cells, or in the kidneys and liver
• For peptides, occurs through proteasomal degradation
• For amines, occurs through deamination (removal of -NH2 group)
• For iodothyronines, occurs through deiodination
Hormone inactive metabolites and their removal from the body
• Aminoacids regained from peptide degradation can be recycled
• Amine metabolites (HVA, VMA, 5-HIAA etc.) are excreted with urine
• Metabolites of steroid and thyroid hormones may undergo further processing in liver (e.g. conjugation with glucuronic acid to make them more hydrophilic)
• Subsequently, hydrophilic metabolites are excreted with urine, while hydrophobic metabolites are excreted with the bile
ENDOCRINE SYSTEM – DETAILED PHYSIOLOGY
• Hypothalamus and posterior pituitary gland as places of neuronal input to the endocrine system
• ADH and oxytocin• Hypothalamic hormones delivered to the anterior pituitary gland (RHs and
IHs)• HPA axis (CRH – ACTH – glicocorticoids)• HPT axis (TRH – TSH – thyroid hormones)• HPG axis (GnRH – FSH & LH – sex hormones)• Growth hormone• Prolactin• Mineralocorticoids• Hormones that regulate calcium-phosphate homeostasis
Hypothalamus receives four general kinds of sensory input information:
• Afferent interoceptive information; raw data (e.g. concerning such parametres as: glucose concentration in the blood, body temperature, plasma osmolality etc.)
• Afferent exteroceptive information; raw data (e.g. external temperature, food availability, time of the day, time of the year etc.)
• Interpreted afferent information - e.g. presence or absence of external stimuli needing avoidance (threats, unfavourable external conditions, pain)
• Feedback information from other endocrine glands (concentration of various hormones in the blood or sensing the effects of their action)
Substances synthetized in the hypothalamus include:
• Peptide or amine hormones released to the portal circulation of anterior pituitary gland (releasing & inhibitory hormones, acting on the anterior pituitary)
• Peptides delivered through axonal transport to the posterior pituitary gland, and there released directly to the blood (ADH and oxytocin)
Releasing hormones (liberins)
• TRH (TSH-releasing hormone)• GnRH (gonadotropins releasing hormone)• Somatoliberin; GH-RH (growth hormone-releasing
hormone)• Corticoliberin; CRH (corticotropin-releasing
hormone)
Note that large amounts of TRH can act as prolactin-releasing hormone (cross-affinity)
Hypothalamic inhibitory hormones
• Somatostatin (inhibits growth hormone release from the anterior pituitary)
• Prolactostatin (inhibits prolactin release from the anterior pituitary)
From chemical standpoint, prolactostatin is dopamine; the rest of hypothalamic hormones are peptides
Posterior pituitary hormones:
• ADH (vasopressin)• OXT (oxytocin)
Vasopressin release activators:
• Increased plasma osmolality (detected by chemoreceptors located within cerebral blood vessels)
• Decreased central blood volume (or effective arterial blood volume)
• Pneumadin; a peptide synthesized in the lungs in response to elevated temperature of the inhaled air
• Some egzogenous substances – e.g. opioids
Inhibitors of vasopressin secretion:
• Decreased plasma osmolality• Decreased temperature of the inhaled air• Increased effective arterial blood volume• Some egzogenous chemicals: e.g. ethyl
alcohol
Main actions of vasopressin:
• Vasoconstrictory effects – through stimulation of V1 receptors in muscular layers of arterioles (V1R -> GPCR -> Gs -> PLC -> IP3 -> Ca 2+ -> smooth muscle contraction)
• Antidiuretic effects – through stimulation of V2 receptors within collecting ducts in renal tubules (V2R -> GPCR -> Gs -> AC -> cAMP -> PKA -> TF -> aquaporins)
• Central pro-cognitive effects, depending on V3 receptor (discovered accidentally during vasopressin suplementation)
Oxytocin:
• Its name derived from greek „oky tokos” which means „quick birth”
• Its release regulated mainly through neuronal pathways• Its actions take part in reproductive functions such as:
ejaculation, sexual pleasure, uterine contractions during delivery, milk ducts contraction during lactation
• Its peripheral actions depend mainly on a stimulatory effects on smooth muscle contraction
• Its central actions may include taking part both in shaping interparental emotional bonds after sexual intercourse and forming emotional bonds between mother and child after delivery and during lactation
Hypothalamic-pituitary-adrenal axis:
• CRH release from the hypothalamus is stimulated by stimuli interpreted as unpleasant or requiring avoidance
• CRH stimulates ACTH release from the anterior pituitary
• ACTH has a trophic action towards all zones of adrenal cortex, and in addition, stimulates cortisol release from fascicular zone of the adrenal cortex
Mechanism of action of ACTH:
• In the whole adrenal cortex: activation of cAMP synthesis through GPCR
• Increased level of cAMP is sufficient to activate most enzymes necessary for glicocorticoid synthesis
• However, to synthesize aldosterone, an additional enzyme is required. This enzyme is not activated by cAMP – this is why ACTH does not stimulate aldosterone release.
Glucocorticoids – basic actions:
• Metabolic actions: - promotion of protein degradation everywhere except
liver - inhibition of glycogen degradation - promotion of gluconeogenesis (de novo synthesis of
glucose from some aminoacids) - hyperglycaemic effect - lipolytic effect in cells expressing GC receptors (most
abundant in fatty tissue located on the extremities)
Glucocorticoids – actions towards hemopoesis and inflammation:
• Inhibitory effect on lymphopoesis and eosinophil production
• Slight activatory effect on other hemopoetic lines• Induction of macrocortin synthesis in target cells• Macrocortin is an endogenous inhibitor of PLA2• Inhibitory effect on capillary permeability and
leukocyte margination• ANTI-INFLAMMATORY EFFECT
Glucocorticoids – feedback actions and central actions:
• Inhibition of CRH and ACTH release through negative feedback
• Increased appetite (orexigenic effect)• Mood-alleviating effect (probably mediated
through CRH release inhibition)• Possibility of central receptor downregulation
in case of long-term excess (a role in the pathogenesis of depression)
Glucocorticoids – actions which may be secondary to their primary actions in case of
excess:• Hyperglycaemia -> insulin release -> risk of metabolic
syndrome (obesity, arterial hypertension, type II diabetes)• Protein degradation -> increased breakdown of Ca 2+ binding
proteins -> risk of osteoporosis• Increased breakdown of collagen and elastin in subcutaneous
connective tissue -> stretch marks on the skin• Increased breakdown of collagen and elastin in small blood
vessels -> subcutaneous microcapillary effusions• Decreased lymphopoesis -> deficiency of cell-dependent
adaptive immunity (being more prone to infections, especially viral infections)
Basic roles of glucocorticoids:
• Counteracting the detrimental effects of unfavourable environmental conditions, mainly through promoting gluconeogenesis, thus providing glucose as a source of energy for the cells taking part in the counteractive response
• Negative feedback of inflammatory response (which is a distressful condition by itself)
Hypothalamic-pituitary-thyroid axis:
• TRH release from the hypothalamus and TSH release from the anterior pituitary can be activated by low external temperature or by low concentration of thyroid hormones in the blood
• TRH stimulates TSH release• TSH stimulates iodide uptake, hormone
secretion, and proliferation in thyroid glandular cells
Mechanisms of TSH actions on thyroid glandular cells:
• Dependent on increased cAMP production (stimulation of TSH-R1):
- increased iodide uptake - increased secretion of thyroid hormones to the blood
Dependent on TSH-R2 and increased induction of PLC: - increased proliferation of thyroid glandular cells; thyroid hyperplasia (goiter)
TSH-R2 has a lower affinity, so in response to TSH in physiological concentrations, only TSH-R1 effects will occur
Thyroid hormones – mechanisms of actions:
• Proteins upregulated by thyroid hormones include:
- sodium-potassium pump - beta adrenergic receptors - UCPs (uncoupling proteins) - Insulin receptors and receptors for growth
factors, including NGF - Catabolic enzymes - SHBG
Thyroid hormones – mechanisms of actions:
• Peptides downregulated by thyroid hormones include:
- TSH - TRH
by negative feedback loop
Thyroid hormones – main effects:
• Dependent on the upregulation of sodium-potassium pump:
- increased rate of secondary active transport - increased rate of carbohydrate absorption
from the small intestine - increased heart rate
Thyroid hormones – main effects:
• Dependent on the upregulation of beta-adrenergic receptors:
- increased lipolysis - increased heart rate - elevated systolic blood pressure - oversweating - central effects (e.g. tachykinesia, hyperalertness) - fasciculations within skeletal muscles
Thyroid hormones – main effects:
• Dependent on the upregulation of UCPs: - decreased ATP production - increased thermogenesis - hyperthermia, heat intolerance - excessive activation of catabolic enzymes (in
response to decreased ATP level) - lower threshold for adaptive vasodilation - loss of diastolic blood pressure
Thyroid hormones – main effects:
• Dependent on the upregulation of insulin receptors:
- shift of the glycaemic curve to the left - more frequent meal ingestion - reflexory stimulation of peristalsis - hyperdefecation
Thyroid hormones – main effects:
• Dependent on the upregulation of catabolic enzymes:
- loss of heart muscle contractility (due to overcatabolism of actin and myosin)
- weakness of respiratory muscles, dyspnea - general weakness - waisting, negative protein balance
Thyroid hormones – main effects:
• Dependent on the upregulation of SHBG: - decreased concentration of free sex
hormones - loss of sex drive - oligomenorrhea
Thyroid hormones – feedback actions:
• Decreased TRH and TSH release• Lack of these effects may promote goiter
formation in case of iodine deficiency (uninhibited TSH release)
• Lack of these effects may promote secondary hyperprolactinemia in case of thyroid insufficiency (uninhibited TRH release)
Main roles of the thyroid gland in physiology:
• To adjust thermogenesis to external temperature• To adjust metabolic rate to thermogenic requirement (i.e. to
external temperature)• To adjust appetite to the metabolic rate• Fine-tuning of the parametres mentioned above in case of
mixed conditions (e.g. low food availability + low external temperature) -> making use of fatty tissue (lipolysis)
• To promote neurogenesis and intellectual development in childhood
• To promote elongation of extremity bones (in combination with IGFs)
Hypothalamic-pituitary-gonadal axis:
• Will be discussed in detail during seminars titled „reproductive system”
Growth hormone (somatotropin) – release activators
• Somatoliberin (GH-RH)• GH-relin• Hypoglycaemia• Chronobiological factors (first half of the
night, deep sleep)
Growth hormone release inhibitors:
• Hyperglycaemia• Increased concentration of FFA in the blood• Somatostatin• Some egzogenous substances (e.g. ethyl
alcohol, atropin)
Growth hormone – primary actions:
• Activation of glycogen degradation -> hyperglycaemia
• Activation of lipolysis -> increased FFA in the blood
• Activation of IGF release from the liver
Growth hormone – secondary actions (IGF-dependent actions)
• Anabolic actions• Promoting cell proliferation• Promoting protein synthesis• Trophic actions on several tissues (e.g. skeletal
muscles and subcutaneous fatty tissue)
Prolactin – release activators:
- meals, sleep, sexual satiation - gestational hormones - neuronal reflexory pathways (during lactation)
Prolactin – release inhibitor:
• Dopamine (through D2 receptor)
Prolactin – main actions:
• Promoting the maturation and development of milk ducts (during pregnancy)
• Trophic (supportive) action on the breast• Inducing sexual refraction• Inhibition of GnRH release from the
hypothalamus (responsible for amenorrhea and supressed sex drive during lactation)
Mineralocorticoids:
• Aldosterone acounts for 99% MC activity in humans• Aldosterone is produced from cortisole in the cells of
glomerular zone of adrenal cortex• Ca 2+ is necessary to activate the last and crucial enzyme on
aldosterone synthesis pathway• The basic factors that increase Ca 2+ concentration within
glomerular zone cells include: angiotensin II and hyperkalemia (elevated concentration of potassium in the blood)
• Therefore, most factors that activate renin production will also activate aldosterone secretion (e.g. arterial hypotension, adrenalin through beta-1-adrenergic receptors)
Aldosterone – mechanisms of action:
- In smooth muscular layers of arterioles – upregulation of receptors for vasoconstrictory agents (V1, alpha1, AT-1)
- In distal renal tubules – upregulation of sodium-potassium exchanger at the luminal site of the tubule epithelium – thus promoting sodium absorption, and at the same time – potassium elimination with urine
Of note:
• ACTH does not stimulate aldosterone secretion, but in the absence of ACTH the whole adrenal cortex would undergone atrophy, making aldosterone production insufficient
• Cortisone holds some cross-affinity to aldosterone receptors, and its excess may sometimes mimick the symptoms of aldosterone excess
Basic roles of aldosterone:
• To prevent hyperkalemia in case of high-potassium diet
• To prevent loss of arterial blood pressure & volume of ECF
• To prevent excessive loss of sodium through the kidneys
Hormonal regulation of calcium-phosphate balance
• Phosphates are abundant in diet (every biomass contains ATP) while calcium is not so much abundant
• Humans are at risk of relative calcium deficiency
• Too little calcium in the ECF would cause tetany -> respiratory insufficiency -> death
PTH:
• Prevents loss of calcium concentration in ECF• Facilitates elimination of phosphate excess with
urine• Facilitates calcium reabsorption from urine• Allows calcium mobilization from the bones (through
activating bone resorption by osteoclasts)• Stimulates calcitriol production in kidneys• Is negatively regulated by calcium concentration in
the blood
Calcitriol:
• Upregulates calcium-binding proteins• Therefore, promotes both calcium absorption
from the small intestine and effective calcium deposition in the bones
Calcitonin:
• Can decrease calcium concentration in the blood in case it is too high
• Does it mainly through activating osteoblasts and accelerating calcium uptake by the bones
• Normally serves only for quick utilization of calcium excess, in case it is present at the moment
• Calcitonin deficiency does not result in hypercalcemia, because in case of accidental hypercalcemia, concentration of ECF calcium is much more controlled through inhibition of PTH release