5 Flashcards
Do cells only make one type of hormone?
No
Hormones are co-expressed, meaning that one cell produces more than one hormone
Are there cells that produce TSH only
no
there is no cells that will produce just TSH ( thyroid stimulating hormone) beta, thus TSH comes from cells that produce other hormones as well
Are there cells that produce GH only?
60-70% GH+ cells express only GH and no other hormones
Are there cells that produce PRL only?
6-16% PRL+ cells express only PRL
WHat is the sexual dimorphism factor of PRL?
Cells that produce PRL only are more found more frequently in females than males
Are two types of gonadotrophs produced by 2 different cells?
Gonadotropin producing cells produce both LH and FSH, no singularity-> Both gonadotrophs are co-expressed
What is a somatotroph?
Somatortropin (GH) producign cells
How is GH stored?
in granules in the cytoplasm of somatotrophs
WHat is the most abundant type of endocrine cell in the anterior pituitary?
somatotroph
Pituitary contains about __-__ mg of GH
Pituitary contains about 5-15 mg of GH
WHat is the release of GH dependent on
on it’s release from storage granules, not on it’s levels of production necessarily
What are the types of GH genes? Where are they found?
The five-member human growth hormone (hGH)/chorionic somatomammotropin (hCS) gene cluster encodes the pituitary-specific hGH-N gene expressed in pituitary somatotropes, and four highly related genes (hGH-V, hCS-A, hCS-B, and hCS-L) that are expressed only in the placenta.
What is so special about the hCS-V isoform?
- non-functional/non-expressed in males
- hCS-V increases midgestation
It is expressed in placenta-> after delivery (no placenta)-> hCS-V disappears from circulation within hours
has an affect on the mother- when levels go up in the gestation- GH levels go down in the mother - after mid-gestation GH levels go don in the mother
How are hGH genes regulated? How are they dipsered in the genome
these are controlled by upstream sequences
these genes are presnet in one region of human genome
What are the 2 forms of GH gene? How do they differ
- Major form 22 kDa (191 a.a);
Shorter isform (20 kD) with aa 32-46 missing, contributes 10% of GH pool - these are the same gene- shorter isoform is produced by post-translational splicing
-There are subtle differences in the spectrum of bioactivities + degree of glycosylation
What can Human GH be used for?
for treatment of pituitary dwarfism
What is the problem with cadaver-sourced GH
prion contamination
GH is secreted by the __ pituitary gland in a __
GH is secreted by the anterior pituitary gland in a pulsatile manner under the acute stimulatory effects of the hypothalamic peptide GH-releasing hormone (GHRH) and the inhibitory effects of somatostatin.
What are the 2 main factors that control GH release (stimulatory and inhibitory)
What is the source of these factors
Hypothalamus releases these factors
stimulatory- hypothalamic peptide GH-releasing hormone (GHRH)
inhibitory - somatostatin
__ and __ neurons integrate stimulatory and inhibitory inputs to regulate pituitary GH secretion
GHRH and Somatostatin neurons integrate stimulatory and inhibitory inputs to regulate pituitary GH secretion
What are some of stimulatory factors that act on GHRH? and thus the release of GH
deep sleep
fasting
hypoglycaemia
gherlin
What are some of suppressing factors that act on SRIF? and thus the inhibtion release of GH
obesity glucose hypothyroidism IGF-1 FFA
What is a treatment that induces GH secretion? How does it affect various sexes
GHRH treatment induces GH secretion (♀response > ♂)
Which hormone inhibits GH secretion
somatostatin
When is 2/3rd of GH released
in slow-wave sleep/deep sleep
What are the GH levels throughout the life stages?
Levels fetus (highest) > child < adolescent (big increase in GH levels) > adult
What is the potency of the effect of GH depended on?
Changes in amplitude (the amount released) but not frequency of pulses
What is the hypothalamus-pituitary-liver axes?
Hypothalamus-> GHRH-> GH production from pituitary-> GH stimulates the production of IGF-1 in the liver
WHat is the master regulator of GH release
hypothalamus
How is GH found in the circulation?
GH is found in circulation in bound to a protein
GH is bound to GHBP – extracellular domain of GHR This also regulates the half-life of GH
How does GH bind to a receptor and phosphorylates it? What happens after phosphorylation
GH is a tyrosine kinase receptor signal that uses adaptor protein-> GH receptor has no auto-phosphorylation capacity-> needs an adaptor
GH receptor uses JAK2
-> JAK2 self-phosphorylates and phosphorylates the receptors
In which form are the ligands who’s receptor needs an adaptor protein found?
Ligands that require an adaptor protein are found in pre-dimerized form, before they bind to a protein and after binding to the receptor, they cannot autophosphorylate -> have to recruit a tyrosine kinase
Which pathways/outcomes can JAK2 lead to?
GH+JAK2-> MAPK-> cell proliferation
GH+JAK2-> PI3K-> glucose metabolism
GH+JAK2-> STAT-> IGF-1
What is the effect of STAT pathway?
STAT is a transcription factors, has multiple target genes including suppressors of cytokine signalling (SOCS)
SOCS are inhibitors of STAT signal - stat signal is this case comes from GH
SOCS thus inhibit GH signalling
SOCS also result in IGF-1 formation which has an inhibitory effect on GH release
What happens to SOCS-2 knockout mice? Why?
They were gigantic
suppressor of cytokine signalling (SOCS) inhibits GHR signalling
What is the direct action of GH
Promotion of cell
differentiation
What is the indirect action of GH
Induction of IGF-I production by liver cells that can act as proliferative and differentiating gene;
also stimulates other proteins that are necessary for this IGF-1 pathway - IGFBP-3 (IGF binding protein) and ALS
How does IGF-1 found in the circulation?
as a bound protein
What is the role of proteases in IGF-1 pathway
proteases free IGF-1 from IGF binding protein
They are also stimulated by GH
WHat is the function of IGF-1
proliferation and differentiation of cells
Where is IGF-1 produced?
mainly in the liver but is also produced locally under the influence of GH (regulation of local growth)
How does GH promotes growth
GH induces growth directly by acting on cells through GH receptors, but most of it comes inderectly from stimulating IGF-1 system
When is IGF-1 growth system important
in childhood
IGF-I levels __ growth rate in children
IGF-I levels parallel growth rate in children
What is the effect of GH and IGF-1 on bones
GH and IGF-I promote growth of long bones at the epiphyseal plates (proliferation (differentiate through calcification) of cartilage cells, i.e. chondrocytes).
When does bone growth finish?
Epiphyses fuse at the end of puberty and longitudinal growth ceases
Does auricular cartillage calcify?
no- it’s a cushioning for bone interaction
GH metabolic effect in adults
optimizes body composition, physical function and substrate metabolism
- regulated partially by GH, but GH influences effects of other genes to regulate these processes
Interacts with insulin to regulate Glu, fat and protein metabolism
GH effect on fat
Enhances lipolysis and FA oxidation – improved during fasting (fatty oxidation of energy is stimulated in muscles
allows for use of non-glucose nutrients- useful in fasting)
GH effect which is beneficial in fasting
- Enhances lipolysis and FA oxidation – improved during fasting (fatty oxidation of energy is stimulated in muscles-> allows for use of non-glucose nutrients- useful in fasting)
- Reduces urea synthesis and excretion – Protein sparing
GH effect on glucose uptake
- Inhibits insulin stimulated glucose uptake
- Also, GH treatment induces insulin secretion and glucose uptake
GH effect on AA uptake and protein synthesis
Increases AA uptake and protein synthesis
Describe IGF-I
IGF-I: GH-dependent
- Produced by the liver and other tissues. IGF-I from the liver is released into the blood stream.
- Other tissues - local production and paracrine/autocrine.
Describe IGF-II
IGF-II: GH-independent - Important in fetal development. Role in adults less clear. May act via IGF-I receptors. May not be important beyond fetal development
Describe IGF-binding proteins
- Secreted by target cells together with specific proteases.
- May regulate bioavailability and turn-over of IGFs
Structure of IGFs is similar to _
Structure of IGFs is similar to insulin
What dictates the bioavailability of IGF-1?
IGF-binding proteins allow tissued to regulate local IGF-I signalling
IGF-I is an endocrine hormone that has a set of binding proteins that bind and hold IGF-I-> not bioavailable
Binding protein proteases can be released by tissues -> affects how much IGF-I is bioavailable
thus levels of IGF-1 released by the liver does not necessarily dictate the amount og IGF-1 available
How do IGF levels vary, are they connected to GH?
IGFs remain relatively constant over long periods despite fluctuations of GH
What are the receptors of Gh? Which pathways can they lead to?
tyrosine kinases with adaptor proteins
Can feed into MAPK, IP3K, JAK/STAT
What are the pathways IGF-1 receptor could lead to?
Acts via intrinsic tyrosine kinase activity, MAPK or IP3K
What is the main difference- GH vs IGF receptors
IGF-1 has auto-phosphorylation activity - phosphorylation occurs instantly,
What is the structure of IGF-1 receptor?
Similar to insulin receptor. Dimer of two glycoprotein subunits (AB)2
What is the structure of IGF-II receptor?
Single-chain spanning the membrane once.
What does IGF-11 bind also?
Also binds mannose-6-
phosphate.
what is the IGF-II activity?
No known signal activity, at least postnatally
WHat is the feedback controls of GH release
Balance between GHRH and somatostatin (GH release inhibiting hormone)
Feedback control by IGF-I on pituitary and hypothalamus
Feedback control by GH by acting upon GHRH
Control by the nervous system:
Control by metabolites
GH release controls by the nervous system?
- Stress (exercise, excitement , cold, anesthesia, surgery, hemorrhage) → surge in GH.
- Sleep induces fluctuations in GH. Secretion every 1-2 h.
Mental stress-> decrease in GH release levels
How do metabolites affect GH release levels?
- Increase: Hypoglycemia (e.g. produced by insulin administration); Amino acids (arginine)
- Decrease: Hyperglycemia (oral glucose), free fatty acids
GH release difference in adults vs young people
younger people have higher amplitudes of release and also more frequent releases
balance between which 2 hormones determine GH release?
Balance between GHRH and somatostatin (GH release inhibiting hormone)
GH vs IGF-1 concentrations through out development
GH concentrations go up, dip and come back up at adolescence, whereas the concentrations of IGF-1 parallel the body growth-> at 20 yo.o IGF concatenations go down
GH and sex hormone interaction
GHR is. downregulated by GH or other factors (sex hormones)
Estrogens inhibit GH signalling by stimulating the expression of SOCS proteins which are negative regulators of cytokine receptor signalling.
WHat are the causes of acromegaly?
Most cases of acromegaly are caused by a noncancerous (benign) tumor (adenoma) of the pituitary gland. The tumor secretes excessive amounts of growth hormone, causing many of the signs and symptoms of acromegaly
Different Effect of glucose on GH levels in people with acromegaly vs normal
Normal: injection of glucose-> response from GH-> initial drop in GH levels followed by a gradual increase
increase in GH secretion
Acromegaly: GH levels stay constant and very high; levels of GH in acromegaly always exceed GH levels in a normal person
such response will not be observed if the patient already has a lot of GH such as in acromegaly
inject insulin -> observe the response
thus insulin tolerance and glucose tolerance tests are used for diagnosis
GH response after insulin induced hypoglycemia: normal vs acromegaly
Normal: after insulin dose GH levels will surge
Acromegaly partial deficiency will be observed
SOCS proteins are negative regulators of __ receptor signalling
SOCS proteins are negative regulators of cytokine receptor signalling
