Hypothalamus-anterior pituitary Flashcards
1
Q
who discovered the pituitary was made up of 2 parts?
A
Rathke (19th century)
2
Q
what are the 2 parts of the pituitary called?
A
- anterior pituitary (adenohypophysis)
- posterior pituitary (neurohypophysis)
3
Q
why is the pituitary considered the master gland?
A
it secrets a lot of hormones
4
Q
who was the first to pioneer the surgical technique to remove part of tumor on the pituitary causing acromegaly through nose?
A
Harvey Cushing
5
Q
what are the functions of the pituitary gland?
A
- growth hormone
- lactation (prolactin)
- action on the Thyroid (thyrotropin or thyroid stimulating hormones TSH)
- action on the adrenals (adrenocorticotropin or ACTH)
- action on the gonads (gonadotropins: Luteinizing hormone LH and Follicle stimulating hormone FSH)
6
Q
why do we refer to the hypothalamus-pituitary axis?
A
although the pituitary was considered as the master gland, it is controlled by the nervous system via the hypothalamus
7
Q
what is the hypothalamus-pituitary axis
A
the link between the nervous and endocrine system
8
Q
what structure separates the hypothalamus and pituitary
A
median eminence
9
Q
what are the 2 difference ectodermal components making up the hypothalamo-hypophyseal tract?
A
- Rathke’s pouch
2. the infundibulum
10
Q
what is Rathke’s pouch?
A
outgrowth of the buccal cavity, detaches and becomes the anterior pituitary
11
Q
how does the infundibulum develop?
A
it develops from an outgrowth of neuroectoderm from the floor of the 3rd ventricle
12
Q
what are the structures that the infundibulum gives rise to?
A
pituitary stalk, median eminence and posterior pituitary
13
Q
the hypothalamus is organized into discrete nuclei. Which are the main ones?
A
- paraventricular nuclei PVN (=PVH)
- supraoptic nuclei SON
- arcuate nucleus Arc
- lateral nuclei
14
Q
which hormones do PVN and SON produce?
A
oxytocin and vasopressin
15
Q
3 characteristics of PVN and SON
A
- large neurons (120-200nm diameter)
- Herring bodies: hormone granules are visible and can be observes traveling down the axons
- terminate in posterior pituitary
16
Q
which nuclei are hypothalamic-hypophyseotropic?
A
- periventricular nucleus PeVH
- PVN (smaller neurons)
- arcuate nucleus Arc
17
Q
where are hypothalamic-hypophysiotropic nuclei located?
A
near the wall of the third ventricle
18
Q
where do the nerves of small PVN, PeVN, Arc found in hypothalamus terminate?
A
in the external layer of the median eminence
19
Q
where are magnicellular neurons located?
A
SON and PVH
20
Q
can you see hormone containing vesicles in parvicellular hypophyseotropic neuron?
A
no unless they are at the axon terminal
21
Q
which hypothalamic hormones are released by PeVN and small PVN?
A
TRH, CRH, Somatostatin
22
Q
which hypothalamic hormones are released by Arc?
A
GHRH, GnRH, Dopamine
23
Q
Mode of action of parvicellular hypophyseotropic neurons (hypothalamus to AP)
A
- axon terminals of hypothalamic neurons release hypophyiotropic hormones in the area of the median eminence
- hormones are taken up by capillary blood vessels
- travel to the anterior pituitary via the portal vein
- hormones enter the AP and trigger the reals of second wave of hormones
- the pituitary hormones enter the blood stream via the venous capillaries
24
Q
which organs do magnicellular neurons act on
A
uterus, kidney, mammary gland
25
which are the second wave hormones involved in the action of the hypothalamus on the Anterior pituitary?
ACTH, TSH, GH , LH, FSH, Prolactin
26
mode of action of magnicellular neurons involved in hypothalamus to posterior pituitary
- posterior pituitary is composed of the axon endings of neurons whose cell bodies are in the hypothalamus
- Hormones (oxytocin and vasopressin) are produced in the cell bodies, packaged into granules which migrate to the ends of the axons located in the posterior pituitary
- stimulation of neurons in the hypothalamus triggers the release of the hormones from the axon tips located in the posterior pituitary
- the hormones are taken up by capillaries ad enter the blood stream
27
how does the hypothalamus secrete these diverse hormones?
through the integration of external [light, temperature, odorants] and internal [blood pressure, osmolality, hormone and glucose levels] cues through circumventricular organs which are windows to the periphery of the hypothalamus, overcoming the blood brain barrier (impermeable to many macromolecules), through direct connection with hypothalamus nuclei.
28
which are circumventricular organs?
- median eminence (ME)
- organum vasculosum of the lamina terminals (OVLT)
- subfornical organ (SFO)
- subcommissural organ (SCO)
- area postrema (AP)
29
characteristics of circumventricular organs
- they have direct connection to hypothalamus nuclei
- rich in blood supply with permeable blood vessels (unlike blood-brain barrier)
- exposed to hormones, metabolites and toxins (i.e. OVLT neurons have estrogen receptors)
30
where do hypothalamic nuclei send outputs to?
regulatory sites: AP, PP, cerebral cortex, premotor and motor neurons in brainstem and spinal cord, and parasympathetic and sympathetic preganglionic neurons
31
role of pineal gland
secretes melatonin
| integrate information from external cues and internal milieu
32
what is the role of the suprachiasmatic nucleus SCN
- circadian pacemaker ("clock") that controls many physiological functions including pineal
- has melatonin receptors - light and melatonin can reset the clock
33
about melatonin
- melatonin concentration follows circadian rhythm
=> pineal gland begins producing melatonin in the evening and melatonin levels peak in the middle of the night
- synthesized from tryptophan
- melatonin receptors are found (almost) everywhere in the human body
34
functions of pineal gland
- core body temperature (entrain body's biological rhythms to the dark-light cycle)
- induction fo sleep
- depression of reproductive activity, inhibition of ovulation and semen production in some animals (questionable role in humans)
- seasonal fluctuation may affect the timing of breeding, migration and hibernation in mammals
35
melatonin is highest in which population?
young population (5-10 years) and decreases with age
36
what are 4 adverse side effects of melatonin?
- daytime sleepiness and hypothermia
- desensitization of melatonin receptors if doses too high
- possible adverse events in those with seizures
- possible interaction with those taking Coumadin/warfarin (anticoagulants)
37
name anterior hypothalamic hormones
- dopamine
- prolactin-releasing hormone PRH
- thyrotropin-releasing hormone TRH
- corticotropin-releasing hormone CRH
- growth-hormone releasing hormone GHRH
- gonadotropin-releasing hormone GnRH
38
characteristics of cells found in anterior pituitary gland
contain alot of endoplasmic reticulum for synthesis of protein/peptide hormones + many secretory granules
39
what are the 5 subgroups of cells found in the anterior pituitary
- corticotroph (15-20%)
- gonadotrophs (10-15%)
- somatotroph (40-50%)
- lactotroph (10-15%)
- thyrotroph (3-5%)
40
product + target of corticotroph
ACTH -> adrenal cortex/gland
41
product + target of thyrotroph
TSH -> thyroid gland
42
product + target of gonadotrophs
LH and FSH -> gonads
43
product + target of somatotroph
GH -> all tissues
44
product + target of lactotroph
PRL -> mammary glands and gonads
45
what is the difference between GH/PRL and TSH?
prolactin and growth hormones are exclusively produced by lactotrophs and somatotrophs respectively, where as there is no one cell that only produces TSH [co-expressed]
46
there is a ..... that can be noted with prolactin. what does it mean?
sexual dimorphism
| aka females have more lactotrophs than age matched males
47
mechanism of action of hypothalamic hormones affecting the anterior pituitary
- short half-life in circulation and fast action
- hormones binds to receptors of target cells in the AP and trigger he release (exocytosis) of stored peptide hormones in granules
- some feedback (mostly negative) control through modulation of receptor numbers
- post-receptor intracellular signaling by G-protein
48
through which pathway do the releasing hormones from hypothalamus act?
GPCR pathway
49
tropic hormones (hormone produced by AP) use ... and ... which leads to an increase in .... and ....
Gs-alpha and Gq-alpha
| which leads to an increase in calcium levels and exocytosis of hormone granules
50
inhibitory hormones (somatostatin and dopamine) act via ....
Gi-alpha
51
.... make up the largest portion of endocrine cells in anterior pituitary
somatotrophs that produce growth hormones
52
pituitary contains about ..... of GH
5-15mg of GH
53
where is the gene hGN-N expressed?
in somatotrophs in anterior pituitary
54
where are the hCS's gene expressed [isoforms A, B, V and L]?
in chorionic somatotropins in placenta
55
what is the result of the transcription/alternative splicing/translation of the hGH-N gene?
2 proteins:
- major 22 kDA form with 191 AA contributing to 90% of the GH pool
- shorter isoform contributing to 10% of GH pool
56
growth hormone releasing hormone GHRH is a .... regulator of GH secretion
positive
57
somatostatin (SST) is a .... regulator of GH secretion
negative
58
GHRH and SST neurons both terminate in .....
median eminence
59
GHRH neuron stimulates ... neuron which stimulates inhibitory neuron ....
NPY neuro stimulates inhibitory neuron SST
60
GH is a target hormone secreted by ..... which are under the influence of .... and ....
sometotrophs, GHRH and SST neurons
61
..... also has a negative feedback like ... to GH secretion
IGF-1 and GH
62
stress (exercise, excitement, cold, surgery, hemorrhage) .... GH
increases
63
hyperglycaemia (oral glucose), free fatty acids .... GH
decrease
64
hypoglycaemia (produced by insulin administration) and amino acids (arginine) .... GH
increase
65
Leptin ... GH
increases
66
ghrelin .... GH
increases and decreases GH
67
mechanism of how ghrelin decreases GH
Ghrelin positively regulates NPY which stimulates SST neuron which is a negative regulator of GH
68
is there a difference in response in terms of GH levels between males and females?
yes -> sexual dimorphism
females respond more than males
-> GHRH treatment induces a greater secretion in GH than males
69
somatostatin .... GH secretion but not ....
inhibits GH secretion but not synthesis
70
why do we refer to bimodal increase when discussing GH secretion
GH levels vary throughout the life: levels fetus > child < adolescent > adult
=> bimodal increase
71
how does GH circulate in the blood?
GH Binding Protein although Gh is a protein hormone - the extracellular domain of GHR
=> increase half life and bioavailability
72
which cell types express GH receptor?
all cell types -> receptors are all over the body
73
growth hormone signalling pathway
RTK signalling pathway with recruitment of tyrosine kinase JAKs
- 1 GH hormone has to bind to 2 receptors
- once hormone binds to receptor dimer, recruitment of tyrosine kinase in form of JAK protein
- JAK proteins phosphorylate cytoplasmic domain of receptor:
1. -> docking site of STAT protein, dimerization of STAT that is phosphorylated will go int nucleus and serve as transcription factor and regulate next level of hormone IGF-1
2. MAPK pathway [cell proliferation genes]
3. IRS/PI3K [glucose metabolism]
4. CoAA [nuclear pro-proliferation genes]
5. Ras/Raf - MEK - ERKs
74
what does GH regulate?
IGF-1, cell proliferation genes, glucose metabolism, nuclear pro-proliferation
75
.... protein inhibits phosphorylation and has a negative feedback on GHR signaling
suppressor of cytokine signaling SOCS
76
.... knockout mouse -> gigantic
SOCS-2
77
what is the direct action of GH effects
promotion of cell differentiation and growth
78
what are the indirect actions of GH effects
- acts on liver and induces expression of IGF-1 that promotes cell division
- IGF-1 levees parallel growth rate in children
- GH and IGF-1 promote growth of long bones at the epiphyseal plates (proliferation of chondrocytes)
- > Epiphyses fuse at the end of puberty and longitudinal growth ceases
79
.... produces 90% of IGF-1
liver
80
how does IGF-1 circulate in blood
IGFBP 1 to 6
81
how is bioavailability of IGF-1 increased?
by the action of proteases that specifically degrade IGFBP locally expressed as this will allow IGF-1 to be free for its signaling
82
what are the metabolic effects fo GH?
- in adults: optimizes body composition, physical function, and substrate metabolism
-> interacts with insulin to regulate lipid, protein, and glucose metabolism
- enhances lipolysis and FA oxidation into acetyl-coA (utilization of lipid for energy)
- reduces urea synthesis and excretion -> protein sparing
- increases AA uptake and protein synthesis
0 inhibits insulin stimulates glucose uptake
83
IGF-1 is .... dependent
GH
84
IGF-1 produced by the liver is released in ....
blood stream
85
IGF-1 produced by other tissues has a ...... effect
paracrine/autocrine
86
IGF-2 is GH .....
independent
87
what is IGF-2 important for?
fetal development
88
stricture of IGFs is similar to ...
insulin
89
what is the main difference between GH-receptor and IGF-1 receptor
GH-receptor acts via recruitment of tyrosine kinase JAK2 and activation off STATs, MAPK or IP3K where as IGF-1 receptor acts via intrinsic tyrosine kinase activity, MAPK, or IP3K
90
which is the largets hormone
prolactin (198 AA vs 191 for GH)
91
which is the most bioactive form of prolactin?
monomeric
92
prolactin levels in males vs females
sexual dimorphism - females have more prolactin than males at any given time but levels reduce with age
93
action of dopamine on prolactin
dopamine from Arc acts as the main inhibitor via dopamine D2 receptors on lactotrophs
94
effect of prolactin on dopamine
prolactin stimulates dopamine response - positive regulation of negative regulator => overall: negative feedback loop
95
which are the positive regulators of prolactin?
TRH, VIP (vasoactive intestinal peptide neurotransmitter) and oxytocin -> positive effect on lactotrophs
96
estrogen .... dopamine neurons and .... lactotrophs
estrogen inhibits dopamine neurons and activates lactotrophs
97
suckling stimulus .... oxytocin neurons and ... dopamine neurons
suckling stimulates oxytocin neurons and inhibits dopamine neurons
98
prolactin signaling (2)
1. ligand-dependent dimerization
2. ligand independent dimerization
both tyrosine kinase receptors which requires a recruitment of tyrosine kinase as JAK - STAT
99
main prolactin function
- PRL is essential for initiation and maintenance of milk production - it stimulates milk production in alveolar epithelial cells
100
which hormones are responsible for alveolar growth during mammary gland development?
prolactin, estrogen, progesterone, and adrenal steroids
101
which hormones are responsible for the duct system development during mammary gland development
GH, estrogen and adrenal steroids
102
PRL levels rise within ..... minutes of suckling and remain elevated for ....
1-3min and ate elevated for 10-20min
103
PRL effect on milk production is .... from neural regulation of milk ejection
distinct
104
which hormone enables milk ejection
instantaneous release of OXYTOCIN in response to suckling
105
which muscle does oxytocin stimulate?
oxytocin stimulates alveolar smooth muscles
106
normally, PRL activates .... neurons but not during lactation
dopamine
107
oxytocin is a hormone from the ... pituitary
posterior
108
which hormone is an example of an end product that can cause a negative feedback loop and switch to a positive feedback loop?
prolactin: negative Feedback loop when stimulates dopamine release from Arc neurons but positive feedback loop during lactation
109
what are other prolactin functions
- involved in regulation of reproductive system
- > if you have high levels of prolactin -> negative feedback on ovarian function causing hypogonadism
- immunomodulation: PRL receptors on B and T lymphocytes and macrophages
- > PRL acts a mitogen and promotes survival
110
how is ACTH synthesized
ACTH is derived by proteolytic cleavage of a large precursor molecule POMC
111
what are the related peptides to ACTH
beta-endorphin, melanocyte stimulating hormones (MSH)
112
function of B-endorphin
morphin-like analgesic activity via m-opioid receptor MOR
113
function of MSH
protection against UV damage via melanocortin receptor MCR1
114
function of ACTH
adrenal steroidogenesis via MCR2
115
what is the molecular pathway of tanning?
- UV DNA damage causes local production of MSH by keratinocytes
- MSH stimulates melanocyte to produce melanin
- melanin transported back to keratinocyte to reduce UV damage and protect the DNA
116
mechanism of action of ACTH
binds to MCR2 in the adrenal Cortex where MRAP is needed
this activates Gs-alpha protein and cAMP-PKA pathway
enhanced mobilization of cholesterol -> increased conversion of cholesterol to prognenolone
cortisol production which has a negative feedback control on the hypothalamus and pituitary
117
what protein catalyzes the movement of cholesterol found in lipid storage to mitochondria
StAR
118
which hypothalamic hormone controls ACTH secretion
CRH corticotropin releasing hormone
(stress info collected by hypothalamus which positively acts on CRH neurones producing CRH going to ME to AP where CRH stimulates ACTH production)
119
CRH action is potentiated by other hormones such as ...
vasopressin
120
cortisol is a .... regulator of ACTH production
negative
121
what do TSH/FSH and LH have in common
they both have 2 protein chains coded by 2 different genes of which the alpha chain is identical. therefore, they are differentiated by their unique beta chains
122
what are the actions of TSH - thyroid stimulating hormone
- regulator of thyroid gland - receptor signaling via G-proteins (cAMP)
- major factor controlling the formation of thyroid hormones
- stimulates metabolism off thyroid follicular cells
123
... and ... neurons stimulate TRH neurons
CRH and POMC
124
... neurons inhibit TRH nurons
NPY
125
.... sensory inputs stimulate TRH neurons
temperature sensory inputs
126
TRH stimulates ... release
TSH
127
TSH-stimulated T3 and T4 have ... feedback on thyrotrophs and TRH neurons
negative
128
what is the action of FSH in females
development of ovarian follicles and estradiol secretion
129
FSH and LH are regulated by ...
GnRH - gonadotropin releasing hormones
130
what is the action of FSH in males
spermatogenesis and estradiol secretin
131
what is the action of FSH in both males and females
stimulates secretion of inhibin - negative feedback on FSH
132
actions of LH in females
steroidogenesis in follicles, induction of ovulation, maintenant of steroidogenesis by corpus luteum
133
actions of LH in males
stimulation of testosterone production in Leydig cells
134
for females, steroid production in follicles requires ....
FSH and LH
135
ovulation requires
mainly LH
136
LH and FSH secretion is ....
pulsatile
137
what is the feedback regulation of estradiol and progesterone on hypothalamus and pituitary?
both positive and negative feedback
138
ACTH deficiency symptoms + diagnosis
malaise, fatigue, anorexia, hypoglycemia
diagnosis: AM cortisol (usually high), Cosyntropin test (injection of exogenous ACTH and see cortisol response), insulin tolerance test
139
TSH deficiency symptoms + diagnosis
malaise, leg crams, fatigue, dry skin, cold intolerance
| diagnosis" T4 and TSH levels
140
Gonadotropin deficiency symptoms + diagnosis
oligo/amenorrhea, diminished libido, infertility, hot flashes, impotence
diagnosis: sexual history, menstrual history, FSH/LH/estradiol/prolactin/testosterone levels (low during deficiency)
141
GH deficiency symptoms + diagnosis
decreased muscle strength and exercise tolerance, diminished libido, increased body fat
diagnosis: insulin tolerance test, GHRH/ariginine test, IGF-1 levels (best test: low levels show GH deficiency)
142
PRL deficiency symptoms
infertility in both male and female, azoospermia in men
143
what causes over-secretion fo hormones of the AP
most commonly due to benign tutors of pituitary (adenomas)
| - they may arise de novo or because of lack of feedback control
144
what are the most common tumors of AP
tumors secreting PRL, GH, ACTH
145
pituitary tumors (adenomas) arise from ... cells
adenohypophyseal cells (AP cells)
146
... tumors are more common at younger age
| ... tumors are more typical in older patients
functional (tutor resulting from very high production of cell types that they're made of) - younger
non-functional - older
147
symptoms of prolactinoma + diagnosis
tumor over-secreting PRL - oligo/amenorrhea, galactorrhea (milk discharge), infertility
decreased libido, headaches, visual field defects often in men and post-monopausal women
diagnosis: PRL level with clinical history (e.g. pregnancy, breast stimulation, stress, hypoglycemia)
148
symptoms of GH-secreting tumors + diagnosis
gigantism and acromegaly
elevated IGFs
diagnosis: IGF-1 levels, oral glucose tolerance test
149
what is the mass effect for functional and non-functional tumors
due to large size of pituitary, impingement on optic chasm - visual field defect - diplopia (double vision), ptosis (drooping eyelids), altered facial sensation
150
symptoms of acromegaly
- visual field defects
- prominent supraorbital ridge
- teeth are separated/lacking
- abnormal glucose tolerance test
- glycosuria/polyuria
- spade-shaped hands and feed
- arthrosis
- hypertrophy of sweat and sebaceous glands
- galactorrhea
151
how do you diagnose pituitary adenomas
- usually delayed due to non-specific nature of symptoms but you can use MRI imaging and there are additional tests that can reveal whether the adenoma is hypo or hyper-functional
+ tests for visual field defects
152
what is the aim of doing an insulin tolerance test for the diagnosis of GH and ACTH deficiency
injection of exogenous insulin in patient causes stress as it induces hypoglycemia. this will cause stress on the brain which allow to evaluate the response of GH and ACTH
153
what does PRL<200ng/ml with large adenoma suggest?
stalk compression as etiology - reduced release of prolactin
154
diagnosis of TSH overproduction
free T4, T3, TSH levels
155
treatment of prolactinoma
dopamine agonist therapy with bromocriptine - binds and activates dopamine receptors which inhibits PRL secretion
156
treatment for acromegaly
somatostatin analogs such as octreotide which reduces GH
157
what are the treatments for deficiencies
replacement of the indicated hormone
