Endocrinology Flashcards
Functions of endocrine system
Homeostasis through metabolism and osmoregulation
Regulate growth and morphological change
Coordinate development
Coordinate reproduction
Facilitate behavioural and social interactions
Endocrine system
Collection of organs, glands and cells that release signals inside bloodstream to affect other cells
Primary function of many hormones is to stimulate release of other hormones: tropic/releasing hormones
Bilaterians
Animals with bilateral symmetry
Nematodes, insects, vertebrates
Endocrine developed as internal communication in earliest bilaterians
Hypothalamic-Pituitary-End Organ axis
Hypothalamus sits on stop: releasing hormones
Act on cells in pituitary: tropic hormones
Target endocrine glands: thyroid, adrenal, gonads, other tissues
Ebers Papyrus
First written description of endocrine disease: diabetes mellitus
Hormae
Greek
“I set in motion”
“I stir up”
Starling uses hormones to describe chemical messengers, produced by an organ which they affect by means of the blood stream
Endocrine vs. Nervous System
Both use chemical secretion
Major difference is mode and specificity or delivery to intended receiver:
Nervous signal goes straight from sender to receiver along axons, rapid
Endocrine signal broadcast generally in bloodstream, only receivers with proper receptor can receive it, slower
Players in endocrine system
- Endocrine glands
- Hormones
- Binding globulins
- Target tissues
- Receptors
General features of endocrine system
- Glands are ductless
- Have rich blood supply
- Hormones are released into blood stream
- Hormones target cells close or far from point of secretion
- Hormone receptors are specific binding sites on or in a target cell, which traduce the signal
Classical endocrine signalling
Endocrine cell releases hormone, transported in blood to target cell which exhibits response
Neuroendocrine signalling
Neuroendocrine cell releases neurohormone which is transported in blood to target cell which exhibits response
Autocrine regulation
Cell releases hormone which diffuses interstitial fluid and acts on itself
Can occur in higher levels in cancer cells
Paracrine signalling
Cell releases hormone which diffuses through interstitial fluid to target cell which exhibits response
Lactocrine signalling
Hormone in milk, transported in blood to target cell which exhibits response
Commercially available pregnancy tests
Western blotting: detecting multiple isoforms of hormone, separated by molecular weight
Antibodies can detect changes in phosphorylation state of target proteins
Immobilized antibodies can be used for immune-purification
Radioreceptor assays
Use cognate receptor in place of antibody for detection of hormone in blood or cell lysates
Labeled hormone competes with unlabelled hormone or unknown samples for binding receptors on cell monolayers or cell lysates
Labeled hormone inculcated with cell monolayers or homogenates and allowed to bond to receptors: chemically cross-linked to form covalent bonds and reposted by SDS-PAGE and visualized
In Vitro Kinase assays
Can be used to detect autophosphorylation or hormone receptors containing tyrosine kinase activity
ie. IGF1 receptor: tyrosine kinase that autophosphorylates in response to IGF binding
Hormone chemical groups
- Amino acid derivatives
- Peptide and protein hormones
- Steroid hormone
- Fatty acid derived hormones
Amino acid derivates
Simplest peptide hormones
Thyroid hormones and catecholamines (epinephrine, norepinephrine, dopamine) are amines synthesized from tyrosine
Melatonin is synthesized from tryptophan
Peptide and protein hormones
Consist of chains of amino acids: also affected by folding of amino acids, affects binding to receptor molecules
Differ greatly in size: TRH 3aa, GH 200aa
Protein hormone processing
Initially synthesized as precursors and cleaved: preproxhormones
Prohormones are cut by pro hormone convertases
Cleavage of initial pro sequence to give hormones
Byproducts of processing are also released along with active hormone
Many prohormones can be synthesized into other end products based on pro hormone convertases present
ie. POMC is converted into ACT in some cells and MSH in other cells
Proinsulin
Cleaves to give insulin and C-peptide
Pancreatic function can be measured using C-peptide
Steroid hormones
Derived form cholesterol
Expression of specific cholesterol-modifying enzymes in steroidogenic tissues determines the type of steroid hormone product
Modify length of side chain, hydroxyl groups, double bonds
Requires multiple enzymatic steps
Prohormone convertases
In cells to process pro hormones into different hormones.
Presence of prohormone convertases determines the outcome hormone
Fatty acid derived hormones
Include prostaglandins and juvenile hormones
Act as autocrine and paracrine factors in the immediate vicinity of their site of production
Distinct from other hormones: do not circulate, act as autocrine or paracrine, secreted and act locally
Lipid soluble hormones
Lipophilic hormones
Steroid and thyroid hormones
Carried by carriers in blood: binding proteins
Must be synthesized as needed as they cannot be stored in cell and are not directly encoded in genome
Derived from dietary, environmental and metabolic precursors
Classical action is entering bilayer and binding with receptors, which enter nucleus and begin gene transcription
Take longer than water soluble hormones
Small and lipophilic
Water-soluble hormones
Lipophobic hormones
Monoamines
Peptide hormones
Protein hormones
Can move freely in blood, but are held in vesicles inside cell
Bind to membrane receptor extracellularly
Binding induces conformational change in intracellular part of receptor
Water-soluble hormone receptor
Hormone bind to membrane receptor extracellularly
Binding induces conformational change in intracellular part of receptor
Newly exposed site interacts with internal proteins and initiates cascade of intracellular messengers: amplification of signal
Causes activation or inactivation of enzymes via phosphorylation or dephospho rylation, opening of ion channels, activation or inhibition of gene expression
Many serve to trigger release of more hormones from target tissue
Receptors must span membrane
Receptor enzymes or GPCR
cAMP
Very common second messenger
GCPR activates adenylyl cyclase
Causes signal amplification
GCPR
Alpha subunit dissociates and activates effector protein
Signalling must be self limiting: GTPase activity of alpha subunit shuts off receptor
50% of all current drugs act on GPCR
Hospira
GPCR drug, induction of labour
Novartis
Sandostatin
GPCR drug, reduces GH secretion
Enzyme-linked cell surface receptors
Intrinsic tyrosine kinase receptor: has enzymatic activity
Tyrosine kinase associated receptor: closely associated with an enzyme
Tyrosine kinase receptors
Use phosphorylated tyrosine to initiate the intracellular signalling cascade
Dimerize and autophosphorylate to act as binding sites for other proteins
ie. Insulin receptor
GH receptor
Tyrosine kinase associated receptor
JAK-STAT pathway: phosphorylates STATS, which dimerize and enter nucleus to induce transcription
Receptor down regulation
Type II diabetes: too much insulin causes internalization of insulin receptors - cell surface receptors can be internalized and degraded in response to prolonged elevation of hormone
Results in decreases responsiveness to hormonal signals
Steroid hormone mechanism of action
- Hormone crosses cell membrane
- Steroid binds to cytosolic receptor which is kept inactive by heat-shock proteins
- Binding alters receptor conformation, releasing HSPs
- Hormone-bound receptors, are free to enter nucleus: act as dimers and bind to hormone response elements in targets genes, recruit coactivator and initiates transcription
- Active reports bind directly to DNA and initiate transcription
- mRNA enters cytoplasm and new protein is synthesized
In absence of hormone, receptor is predominantly cytosolic
Thyroid hormones act similar to steroid hormones, but receptors are generally always in nucleus
Classical nuclear receptors for steroid and thyroid hormones
Share common series of domains, referred to A-F
Determine function
Structure differs in C terminal region: mediate activation function of these hormones and can recruit different regulators
Repressor hormones
Recruit corepressor molecules
Modify histones causing DNA to be more compact
Ligand-dependent activation of gene expression
Ligand-bound nuclear receptor communicates stimulatory signals to general transcription factors on the genes which it is bound
Ligands specifically recruit co-activator proteins to receptor ligand binding domain which increases the rate of transcription
Best understood are p160 family of Histone Acetyltransferases
Lipid soluble protein receptors
Ligand-activated transcriptional regulators serving to translate cues from external and internal environments into gene expression
Classical lipid soluble hormones
Steroid hormones, thyroid hormones
Can have multiple receptor isoforms for single hormone
Lipid soluble vitamins
Vitamin D and Vitamin A
Mutations in nuclear receptors
Can affect binding affinity or target gene recognition
Ie. Androgen receptor is target of mutations that affect sexual development, function and fertility caused by nonsense mutation in ligand binding domain
PAIS
Partial androgen insensitivity
Ambiguous genitalia
MAIS
Mild androgen insensitivity
Normal genitalia with oligospermia
Posterior pituitary
Outgrowth of hypothalamus
Secretes oxytocin and vasopressin: act on target tissues in periphery
Tropic
Cause release of another hormone
Trophic
Cause increase in size or affect growth
Magnicellular neuron
In SON and PCH
Release vasopressin and oxytocin: target kidney, uterus, mammary glands
Paricellular hypophyseotropic neuron
Located in PeVH, PVH
Releases trophic hormones: ACTH, TSH, GH, LH, FSH, prolactin: anterior pituitary gland
Hypothalamic projection neuron
Located in PVH, LHA, Arc
Neuronal targets
Neural pituitary
Site of storage of vasopressin and oxytocin
Synthesized, transporter, and stored here
Released when cells are depolarized
Target of vasopressin is ADH: kidney and water reabsorption
Oxytocin targets uterus and mammary lands
(+ posterior)
Anterior pituitary
6 different hormones
Regulated by releasing factors (hormones) that are released on the capillary bed
Leptin
Secreted by adipose to stimulate satiety
Mouse models of leptin: mutation in leptin gene causes obesity
Most of us are leptin resistant, as we have more fat than necessary
Similar (rare) gene mutations lead to massive obesity in humans
Suprachiasmic nuclei
Major nuclei of the hypothalamus responsible for the generation of the circadian rhythm
Direct and indirect inputs to the SCN proud information about day/night cycles
Endocrine rhythms
Most endocrine hormones are secreted in rhythmic fashion on ~24 circadian cycle
These cycles are free running: driven by intrinsic biological clock
Can be adjusted by external cues: light/dark cycles
ie. hormones of female reproductive cycle
Can even be seasonal: animal mating
Ultradian
Less than a day
Infradian
More than a day
Diurnal
Around a day
Melatonin
Mild hypnotic
Maintain sleep patterns: shifts during changes in sleep cycle
Jet lag results in phase shift of diurnal secretion of melatonin
Synthesized from tryptophan and secreted by pineal gland in circadian pattern in response to light
ADH
Arginine Vasopressin
Acts on kidney to promote water reabsorption: regulation of water homeostasis
Stimuli for secretion also increases mRNA content in the magocellular neurons: synthesized from preprohormone
Responsive to changes in blood osmolality and blood volume singled by central osmoreceptors and peripheral volume receptors
May also have central effect on behaviour unrelated to peripheral effects
Oxytocin
Stimulates smooth muscle contractions in uterine (most powerful uterotonic stimulant) during expletive phase of parturition and mammary tissue to regulate labor and milk let down
Stimuli for secretion also increases mRNA content in the magocellular neurons: synthesized from preprohormone
Used clinically
Numerous actions in CNS
Neurophysin
Controls transport of neurosecretory vesicles holding oxytocin and ADH to posterior pituitary along microtubule tracts
Milk let down
Suckling is requires for milk let down in most species
Oxytocin secretion and milk let down are known to occur by physiological stimuli in humans: preparing for nursing, hearing crying
If oxytocin is not secreted, only 20-30% of stored milk is released during nursing
Maternal behaviour
Coincident with parturition and location in most mammalian species
Oxytocin is increased in various areas of the brain that are thought to be sites of regulation of material behaviour
Oxytocin as neuromodulator
Targets hippocampus and amygdala
Interacts with reward-processing circuits in the nucleus accumbent and ventral segmental area
Exerts anxiolytic affects via direct activation of oxytocin receptors expressed in serotonergic neurons of the raphe nuclei
Intranasal administration of oxytocin
Promotes trust and cooperation
Such effects may be limited to in-group members and do not extend towards out-groups
Rodents lacking forebrain oxytocin receptors
Recognize but no longer discriminate between in-group and out-group stimulus rodents
rs237887
Common SNP in this oxytocin receptor is strongly associated with facial recognition memory in humans
Common polymorphism in oxytocin receptor gene OXTR is associated with human social recognition skills
Cellular mechanism of AVP-mediated water conservation
AVP activated V2 and GPCR (V2R) leading to cAMP mediated activity of PKA
Phosphorylation of aquaporin 2 (AQP2) water channels leads to their insertion in the luminal cell membrane
Corticotropin releasing hormone (CRH)
Stimulates secretion of ACTH (to adrenal) from anterior pituitary
Thyrotropin-releasing hormone (TRH)
Stimulates secretion of TSH (to thyroid gland) from anterior pituitary
Growth hormone releasing hormone
Stimulates secretion of GH (to musculoskeletal system) from anterior pituitary
Stimulates somatotrophos to release GH stored in secretory granules by raising cAMP and Ca levels
Somatostatin
Inhibits secretion of GH from anterior pituitary
Acts by inhibiting adenylyl cyclase and lowering Ca
Gonadotropin releasing hormone
Stimulates secretion of LH and FSH (to gonads) from anterior pituitary
Dopamine
Inhibits secretion of prolactin from anterior pituitary (to mammary)
Culturing non-neural head ectoderm
With hypothalamic neural ectoderm
Leads to spontaneous formation of functional pituitary tissue
Gradients of paracrine factors
Determine the expression of pituitary specific genes encoding transcription factors with specify cell fate
Model for cell lineage determination by cascade of transcription factors
Trophic cells are depicted with transcription factors known to determine cell specific human or murine gene expression
Defect in gene PROP1
Distinct phenotype consisting of absence of Pit-1-dependent lineages
Dramatically reduced number of gonadotropes
Deficiencies of GH, PRL, TSH, LH and FSH
Glycoproteins of anterior pituitary
LH, FHS, TSH, hCG (LH but only produced in placenta)
Contain two subunits: alpha and beta
POMC derivatives (anterior pituitary)
ACTH, MSH, endorphins
Hormones derived from pro-opiomelanocortin
Processing is tissue dependent: presence of particular pro hormone convertases
Cytokine family (anterior pituitary)
Related GH/prolactin family
Structurally related to cytokine signalling molecules of the immune system
Includes GH, PRL, and several related hormones specifically expressed by the placenta in pregnancy ( Chorionic somatomammotrophins and placental GH variant)
Feedback of parathyroid hormone and serum calcium
High concentration of Ca inhibits parathyroid hormone secretion
Primary endocrine disease
Loss of negative feedback in peripheral gland
Secondary endocrine disease
Loss of negative feedback in pituitary gland
Tertiary endocrine disease
Loss of negative feedback in hypothalamus
Growth hormone/prolactin family
Group of structurally related signalling molecules (cytokine)
Includes GH, PRL, and several hormones specifically expressed by placenta in pregnancy
Prolactin: 16% homology, cannot bind to growth hormone receptor but all others can bind to prolactin receptor
Bind to cytokine receptor homodimers
Prolactin
16% homology to GH/PRH family
Cannot bind to growth hormone receptor but all others can bind to prolactin receptor
Best understood in milk production
Bind to cytokine receptor homodimers
Growth hormone
Primary target is liver to secrete insulin like growth factor: they act on tissue to cause growth
Negative feedback loop with somatostatin
GH is released in pulses and in response to aerobic exercise
Most important determinant of post-natal growth
Knock out has little effect on birth weight
PRL-R agonists
Mammary gland/lactation
Epithelium growth and differentiation
Corpus luteum maintenance
Pregnancy dependent brain function: maternal behaviour in pregnancy
Pancreatic function: stimulate growth of eyelets and insulin
Uterine gland development
Angiogenesis
Trophoblast development and function
Modulation of maternal physiology
Regulation of expression of insulin like growth factors: majority of prenatal growth effects of GH/PRL family are mediated by PRL-R
JAK2
Receptor associated tyrosine kinase: activated by GH, PRL, CS binding to cytokine receptor homodimers
STATs
Signal transducers and activators of transcription
Activated by cytokines
STATs bind SH2 domains to phosphorylated tyrosine in activated receptor-JAK complexes
Phosphorylated and homo or heterodimerize with other STAT proteins and move into nucleus
Bind gamma-activated sequence-like elements in the promoters of cytokine-responsive genes
Insulin-like growth factors
Released from liver in response to GH
Circulate as complex with major IGF proteins
Act on number of target tissues to promote growth
Structurally similar to insulin: maintain C region unlike insulin
Attach to receptors structurally similar to insulin
Growth hormone binding protein
Similar to receptor
Circulate together
Interacts with receptors in muscles and adipose
M: diabetic genie, antagonizes affect of insulin
A: stimulates digestion of fat, decreases glucose intake
Indirect and direct actions of GH
Direct: GH acts direction on target tissues
Indirect: causes IGF to act on target tissues
Growth at puberty
Associated with significant increase in GH and IGF1
IGF1
Postnatal growth is associated with GH-dependent rise in serum IGF1 levels which peak around puberty
Major circulating form of IGF
Mutation in gene result in GH-unresponsive growth retardation and elevated serum GH levels: loss of IGF1 negative feedback
IGF2
Major determinant of prenatal growth
IGF2 knock outs have lower birth rates
IGF1 receptor
Can bind IGF1 and IGF2
Predominant IGF1 binding
Insulin and IGF1 receptors are heterotetramers, joined by disulfide bonds: cytoplasmic portions of beta subunits have tyrosine kinase domains and autophosphorylation sites
Different signals depending on cell types and receptor levels
IGF2 receptor
Does not have tyrosine kinase domain
Single polypeptide
Sequesters and destroys excess IGF2
Different signals depending on cell types and receptor levels
Lower levels of IGF2R show higher birth rate
Insulin receptors
A and B, used equally by insulin
A is more used by IGF
IGF binders
At least 6
Circulatory binding, inhibitory (restrict access to receptor), stimulatory (present to receptor), proteases that cleave IGF binding proteins
Most IGF is complexed with one or more IGF binding proteins
IGF independent actions of IGFBP have also been described
Over secretion of GH before puberty
Giantism
Linear body growth, hyperglycaemia, TII diabetes, overgrowth of internal tissues
Heart has trouble maintaining circulation
GH excess can be traced with somatostatin analogies i.e. octreotide
Over secretion of GH after puberty
Acromegaly Thickening of flat bones Bone plates do not fuse Clubbed toes GH excess can be traced with somatostatin analogies i.e. octreotide
Treatment of GH insufficiency
Supplement is current treatment
Now uses synthesized GH: used to take form cadavers but canceled in 1987 after incident of brain wasting disease
In adults: increases muscle mass, decreased adiposity and improved nitrogen balance, could be treatment for aging
Efe people
Ituri rainforest
Considered by mitochondrial DNA analysis to be one of the oldest races on earth
Shortest
GH status and lifespan
Increase in lifespan
No cancer or diabetes
