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Endocrinology > 3.1 Development and Puberty - GH > Flashcards

3.1 Development and Puberty - GH Flashcards

1
Q

what was the first functional association with pituitary tumors?
- when? by who?
- solution?

A

Pierre Marie (french scientist) associated pituitary tumors with acromegaly (overgrown bone structures disorder) in 1886
- 1909: Harvey Cushing (surgeon) pioneered modern neurosurgical techniques and removed part of the pituitary (removed tumor) in an acromegaly patient and noticed improvement

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2
Q

Evans and JA Long (1921): injection of crude extracts of the pituitary gland in animals causes what?

A

causes increased growth!

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3
Q

what 2 things led to the discovery of the growth hormone?

A
  1. Pierre Marie associated pituitary tumors with acromegaly
  2. injection of crude extracts of the pituitary gland in animals causes increased growth
    - growth hormone = 1st pituitary hormone
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4
Q

name 7 hormones from the pituitary and their general pituitary function

A
  1. Growth hormone –> growth and development
  2. prolactin (PRL) –> lactation
  3. thyrotropin/thyroid stimulating hormone (TSH) –> action on the thyroid
  4. adrenocorticotropin (ACTH) –> action on the adrenals
  5. gonadotropins: Luteinizing hormone (LH) and follicle stimulating hormone (FSH) –> action on the gonads
  6. oxytocin (OXY) –> smooth muscle contraction
  7. Vasopressin (AVP) –> body fluid homeostasis
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5
Q
  • why is pituitary considered the conductor of the endocrine orchestra/main endocrine gland?
  • what controls the pituitary?
A
  • bc it regulates other organs –> these other organs basically regulate everything in the body
  • the nervous system via the hypothalamus controls the pituitary –> hence the name “hypothalamus-pituitary axis” –> connection btw neurological regulation and endocrine regulation
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6
Q

what are the 2 main parts of the pituitary?
- where is the pituitary encased?
- what is the part connecting hypothalamus and pituitary?

A
  1. anterior pituitary (adenohypophysis) –> glandular part of the pituitary
  2. posterior pituitary (neurohypophysis) –> terminal endings of neurons coming from hypothalamus
    - in the hypophyseal fossa in sella turcica of sphenoid bone –> Turkish saddle
    - median eminence (ME)! important!
    *also infundibulum below ME
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7
Q

what is another technical name for pituitary?

A

hypophysis
- means: growth/enlargement below the hypothalamus

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8
Q
  • from which tissue ish are the hypothalamus and pituitary developed?
    1. how does pituitary develop?
    2. how does hypothalamus develop?
A
  • hypothalamus = neuroectoderm (?)
  • pituitary = ectoderm
    1. ectodermal thickening in the pharyngeal opening (22 days) –> starts to invaginate to form the Rathke’s pouch to become the glandular structure in the sella turcica (42 days)
    2. neuroectoderm becomes neurohypophysis primordium (60 days) –> develops into the hypothalamus ish
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9
Q
  • what is a nuclei?
  • what are the 4 main nuclei in the hypothalamus
A
  • nuclei (CNS) = area where group of neurons have similar connections and functions VS ganglions in peripheral nervous system
    1. paraventricular nuclei
    2. supraoptic nuclei
    3. arcuate nucleus
    4. ventromedial nucleus
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10
Q

what are the 2 types of nuclei in hypothalamus? subnuclei?

A
  1. HYPOPHYSIOTROPIC NUCLEI
    - PVN + Arc + periventricular nucleus (PeVN)
  2. NEUROHYPOPHYSEAL NUCLEI:
    - Supraoptic nucleus (SON) + PVN
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11
Q

describe hypophysiotropic nuclei
- involved in what?
- sub nuclei?
- located where?
- size of neurons? granules?
- nerves terminate where?

A

HYPOPHYSIOTROPIC NUCLEI
- nuclei involved in regulation of pituitary
- PVN + Arc + periventricular nucleus (PeVN)
- located near wall of 3rd ventricle
- smaller neurons –> hormone granules containing peptide hormones can only be observed in axon terminal
- nerves terminate in the median eminence

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12
Q

describe neurohypophyseal nuclei
- sub nuclei?
- size of neurons? where?
- produce which 2 hormones)
- hormone granules visible?

A

NEUROHYPOPHYSEAL NUCLEI:
- Supraoptic nucleus (SON) + PVN
- large neurons (120-200nm diameter) terminate in posterior pituitary
- neurons produce oxytocin and vasopressin (produced/gene expression in cell body –> travel down axon for exocytosis)
- hormone granules are visible and can be observed travelling down axons

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13
Q

what are the hypophysiotropic hormones produced by each subnuclei?

A

PeVH and PVH:
- Thyroid releasing hormone (TRH)
- Corticotropin releasing hormone (CRH)
- somatostatin
Arcuate nucleus:
- Growth hormone releasing hormone (GHRH)
- gonadotropin releasing hormone (GnRH)
- dopamine

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14
Q

HYPOTHALAMUS –> ANTERIOR PITUITARY
- type of neuron ish?
1. axon terminals of hypothalamic neurons release which type of hormones where? –> through simple exocytosis that depends on what?
2. these hormones are taken up by what? to travel where? via what?
3. what do the hormones do once they get there?

A
  • parvicellular hypophyseotropic neuron
    1. axon terminals of hypothalamic neurons release hypophysiotropic hormones (TRH, CRH, somatostatin, GHRH, GnRH, dopamine) in the area of the median eminence (has rich blood supply)
    2. hormones are taken up by capillary blood vessels –> travel to the anterior pituitary via the portal vein
    3. hormones enter the anterior pituitary and trigger the released of a 2nd wave of hormones –> pituitary hormones enter the blood stream via the venous capillaries –> carry blood from anterior pituitary to the heart –> then to whole body
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15
Q

HYPOTHALAMUS –> POSTERIOR PITUITARY
- type of neuron ish?
- which sub nuclei?
- posterior pituitary composed of what?
- which hormones are produced?
1. where are they produced? –> what happens after?
2 how are they released? ie what triggers

A
  • magnicellular neuron
  • SON and PVH
  • composed of axon endings of neurons whose cell bodies are in the hypothalamus
  • oxytocin and vasopressin
    1. hormones are produced in cell bodies, packaged into granules which migrate to the ends of the axons located in the posterior pituitary
    2. stimulation of neurons in the hypothalamus triggers the release of the hormones from the axon tips located in the posterior pituitary –> hormones enter blood stream via the venous capillaries
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16
Q

name some important hormones from hypothalamus nuclei
- 9 that we will see in class

A
  • oxytocin
  • vasopressin
  • corticotropin-releasing hormone (CRH)
  • thyrotropin-releasing hormone (TRH)
  • gonadotropin-releasing hormone
  • growth hormone-releasing hormone
  • melanocortins
  • prolactin
  • somatostatin
    + a lot more!!!!
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17
Q

what is the blood brain barrier?
- useful for what? BUT…

A
  • refers to reduced permeability of endothelium of brain blood vessels
  • useful bc neurons highly susceptible to toxins BUT hypothalamus needs info from the rest of body
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18
Q

name 5 circumventricular organs
- surround what?

A
  1. organum vasculosum of the lamina terminalis (OVLT)
  2. subfornical organ (SFO)
  3. median eminence (ME)
  4. subcommissural organ (SCO)
  5. area postrema (AP)
    - surround ventricles (fluid filled cavities in brain)
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19
Q

what are 4 characteristics of circumventricular organs?
- example ish?

A
  1. have direct connection to hypothalamus nuclei
  2. rich blood supply
  3. blood vessels are permeable!!! unlike blood-brain-barrier –> more factors can regulate/reach these organs
  4. exposed to hormones, metabolites and toxins
    - GnRH producing cells –> don’t have estrogen receptors –> but OVLT neurons have estrogen receptors –> OVLT has control of GnRH
20
Q
  • hypothalamus ______ peripheral signals to _________ peripheral functions
  • hypothalamus receives sensory inputs from (2) + examples
  • hypothalamus sends outputs to regulatory sites (5 ish)
A
  • integrates peripheral signals to regulate peripheral functions
    1. external environment: light, nociception, temperature, odorant
    2. internal environment: blood pressure, blood osmolality, blood glucose and hormone levels
  • anterior pituitary gland, posterior pituitary gland, cerebral cortex, premotor and motor neurons in the brainstem and spinal cord, parasympathetic and sympathetic preganglionic neurons
21
Q

hypothalamic hormones:
- short/long half-life? slow/fast action?
- what do the hormones do? –> triggers what?
- post-receptor intracellular signaling by what pathway?
- how to regulate hormone signaling?

A
  • short half-life in circulation (very difficult to detect hypothalamus hormones in blood supply –> fast action
  • hormones bind to receptors of target cells in anterior pituitary and trigger release (exocytosis) of stored hormone granules
  • by G-proteins! through GPCR
  • feedback control through modulation of receptor numbers! (ie: hypothalamus –> hormones.1 –> GPCR: pituitary –> hormones.2 –> negatively regulate hypothalamus)
22
Q

anterior pituitary:
1. releasing hormones: 2 G proteins –> lead to (2)
2. inhibitory hormones: which 2 hormones via which G protein?

A
  1. Gsa and Gqa –> lead to increased Ca2+ levels and exocytosis of hormone granules
  2. somatostatin and dopamine act via Gia
23
Q
  • which method revels that endocrine cells in anterior pituitary gland appear like peptide hormone secreting cells?
  • which 2 methods reveal that there are a diversity of endocrine cells/subgroups of cells? –> same results?
A
  • electron microscopy
  • staining for particular hormone by immunochemistry + single-cell RNA sequencing
  • similar results! (ie lactotroph: 10-15% vs 6-16%) even if some differences
24
Q

what are the 5 endocrine cell types of anterior pituitary gland?
- population % (from immunohistochemistry)
- product?
- target?

A
  1. CORTICOTROPH:
    - 15-20%, ACTH
    - adrenal gland
  2. TYROTROPH:
    - 3-5%, TSH
    - thyroid gland
  3. GONADOTROPH:
    - 10-15%, LH, FSH
    - gonads
  4. SOMATOTROPH:
    - 40-50%, GH/somatotropin
    - all tissues, liver
  5. LACTOTROPH:
    - 10-15%, PRL
    - mammary glands and gonads
25
Q

single cell RNA sequencing data:
- cells __________ multiple hormones –> ie?
- no unique _____ cells
- 60-70% _____ cells only express _____
- 6-16% _____ cells express only _____
- sexual dimorphism: males vs females: more PRL+ or GH+ cells?

A
  • cells coexpress multiple hormones –> ie both gonadotropins are co-expressed/expressed from the same cell type
  • no unique TSH cells –> ie if produce TSH, also produce other hormone
  • 60-70% GH+ –> GH
  • 6-16% PRL+ –> PRL
  • males: more GH+ than PRL+ cells
  • females: more PRL+ than GH+ cells
26
Q

what are the most popular/largest portion of cells in the anterior pituitary?
- secrete and produce which hormone? (what type? stored in what?)
- pituitary contains about ___-___ mg of that hormone

A
  • somatotrophs
  • secrete and produce growth hormones –> peptide hormone –> stored in granules
  • 5-15 mg
27
Q

there’s a region where there are multiple genes that encode for GH –> what is it called?
- this region codes for 2 types of GH:
- which 2 types? expressed where?
- which one is the major form? vs minor form? which one is bigger/shorter?
*between the 2: subtle differences in spectrum of __________ and degree of ____________

A
  • GH locus!
    1. hGH-N (human GH - N type)
  • expressed in pituitary
  • Major form (90% of GH we see): 22 kDa, 191 aa
    2. chorionic somatotropins: hCS-A/V/C/L (isoforms)
  • expressed in placenta
  • shorter isoform: 20 kDa, with 32-46 aa missing. 10% of GH pool
    *subtle differences in spectrum of bioactivities (affinity to bind to GH receptors) and degree of glycosylation
28
Q

human GH prescribed/used for treatment of what?
- what is now being used?

A
  • treatment of pituitary dwarfism (that results in stunted growth in children)
  • recombinant GH is now being used –> start of the biotech industry (Genentech)
29
Q

what are the 2 neurons that terminate in the ________ _________ that regulate GH secretion?
- from which nucleus? what are their roles?
* what tells you how much GH is secreted/what controls both these neurons?

A
  • terminate in median eminence
    1. GHRH (growth hormone releasing hormone)
  • from arcuate nucleus
  • positive regulator –> tells somatotrophs to secrete GH
    2. Somatostatin neurons (SST neurons)
  • from periventricular nucleus (PeVN)
  • inhibits GH release
  • the balance between GHRH and somatostatin tells you how much GH is secreted –> this balance is fine tuned by nPY neurons (positively regulates both GHRH and somatostatin neurons
30
Q

which 2 hormones (not from neurons) regulate GH secretion?

A
  1. GH has negative feedback on its production –> GH acts upon somatotrophs, GHRH neurons, SST neurons and nPY neurons (?)
  2. IGF 1- (insulin like growth factor 1) has negative feedback control on pituitary
31
Q

neural and metabolite control of GH secretion:
- 5 ish increase GH
- 2 decrease GH

A

INCREASE:
- stress (exercise, excitement, cold, anesthesia, surgery, hemorrhage, starvation) –> by way of regulating GHRH and SST neurons
- insulin
- amino acids (especially arginine)
- leptin (hormone from adipose tissue)
- ghrelin (hormone from stomach)
DECREASE:
- oral glucose
- free fatty acid

32
Q
  • GHRH treatment induces GH secretion –> sexual dimorphism?
  • somatostatin inhibits GH _________ but NOT GH ________
  • when is GH secreted? what type of secretion?
  • compare levels of GH in fetus, child, adolescent and adult
A
  • women response > men response
  • inhibits GH secretion (dependant on exocytosis of granules) but not synthesis by the somatotrophs
  • 2/3 in slow wave sleep (at night!) –> episodic/pulsatile secretion: quick increase/decrease at periodic frequencies
  • fetus > child < adolescent > adult
33
Q

does GH have a binding protein? explain

A
  • yes! GHBP!
  • even if GH is a peptide, needs binding protein to circulate in blood –> most GH in blood are bound to GHBP
  • main form of GHBP = extracellular domain/ectodomain of GH receptor –> not a covalent bond btw GH and GHBP
  • there’s another form that has lower affinity
  • main role of GHBP is to increase half-life/decrease metabolic degradation of GH
34
Q

GH is released in a ________ fashion
- 2 characteristic
- which one changes vs doesn’t?

A
  • pulsatile fashion!
    1. frequency: ie 4 peaks per day –> number doesn’t change throughout life (for GH)
    2. amplitude/height of a pulse: pulse heights lower in adults vs children
35
Q

what is the direct action of growth hormone?

A

promotion of cell proliferation and differentiation
- GH binds to receptors on cells involved in vertical growth –> tells mesenchymal stem cells in bone to differentiate into chondrocytes to form bone

36
Q

indirect actions of growth hormone –> through which axis?
- induction of which hormone (A) from which organ –> promotes cell ________/___________
- hormone (A) levels parallel what in children?
- ______ and _______ promote growth of ______ ______ at the _______ plates (proliferation of which type of cells?)
- _______ fuse at the end of _______ and longitudinal growth ceases

A
  • hypothalamus-pituitary-liver axis
  • induction of IGF-I that promotes cell division/function
  • IGF-I levels parallel growth rate in children –> better predictor of growth rate than GH: more increase in IGF-I during growth spurt period than increase in GH
  • GH and IGF-I promote growth of long bones at the epiphyseal plates (proliferation of chondrocytes)
  • epiphyses fuse at the end of puberty
37
Q

2 types of insulin-like growth factors
- which is GH dependent/independent?
- produced by which organ?

A
  1. IGF-I –> GH-dependent
    - produced by liver –> released into bloodstream (bc liver doesn’t have many IGF-I receptors)
    - produced by other tissues –> local production and paracrine/autocrine –> doesn’t enter bloodstream and impact other tissues: act locally
  2. IGF-II –> GH-independent
    - important in fetal development
    - role in adults less clear –> may act via IGF-I receptors but not sure
38
Q
  • structure of IGFs is similar to ________
  • do IGF have binding proteins?
  • is IGF secretion pulsatile like GH?
A
  • insulin!
  • yes! IGF-binding proteins expressed along with IGF-I –> BP inhance half-life
  • nope. IGFs remain relatively constant over long periods despite fluctuataions of GH
39
Q

what regulates local bioavailability of IGF-I?
explain!

A
  • target cells express specific proteases of binding proteins that regulate local bioavailability of IGF-I
    1. IGF-I, IGFBP and ALS (helps binding btw IGF and IGFBP) expressed in liver
    2. IGF-I and IGFBP bind together in bloodstream = not bioavailable
    3. proteases cleave and degrade IGFBP to make IGF free for biosignaling
  • tissue response to GH regulated by amount of proteases produced!
  • increased protease = increase free GH
40
Q

compare GH and IGF receptors
- act via what pathway?

A

GH-receptors:
- act via recruitment of tyrosine kinase –> JAK2 + activation of STATs, MAPK or IP3K
- extracellular domain circulates and acts as binding protein
IGF-I receptors:
- similar to insulin receptor –> receptor tyrosine kinase
- acts via intrinsic tyrosine kinase activity –> IRS –> MAPK or IP3K

41
Q

what promotes GHR signalling? vs what inhibits it?

A

INHIBITS:
- STAT pathway from GH receptor = TF –> one of main target = suppressor of cytokine signalling (SOCS) –> inhibits GHR signalling
*SOCS knockout mice –> gigantic! bc no inhibition of GHR
PROMOTES:
- IGF1 inhibits internalization/desensitization of GHR = more GHR at cell surface = promotes GHR signalling

42
Q

metabolic effects of GH: in adults, GH necessary for 3 things
- GH interacts with which hormone to regulate metabolism of 3 metabolites

A
  1. optimizes body composition
  2. optimizes physical function
  3. optimizes partitioning of substrates/substrate metabolism
    - interacts with insulin to regulate lipid, protein and glucose metabolism
43
Q

how does GH affect substrate metabolism/partitioning?
1. enhances (2) + explain
2. reduces (2)
3. increases (2) (related to #2)
4. inhibits smtg BUT “GH treatment” induces smtg else

A
  1. enhances lipolysis and FA oxidation
    - GH promotes hormone sensitive lipase = increases release of non-esterified FA –> can be used in muscle where FA oxidation is promoted by GH
  2. reduces urea synthesis and excretion –> decrease aa catabolism/nitrogen cycling = inhibits use of aa as E source = protein sparing
  3. increases aa uptake and protein synthesis
  4. inhibits insulin stimulated glucose uptake BUT “GH treatment” induces insulin secretion leading glucose uptake…
44
Q

GH promotes more of which substrate utilization?

A

fats! vs proteins and carbs

45
Q

how can GH inhibit insulin stimulated glucose uptake but also induce secretion of insulin leading to glucose uptake?

A

context dependant!
- when fasting: glucose levels are done, insulin levels are low –> need more lipid for E –> increase GH production/entry into cells
- GH to liver = promotes gluconeogenesis = increase glucose = increase insulin (?)
*will be more clear when we talk about glucose metabolism

Endocrinology (14 decks)

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