Week 26 HPA Flashcards
1
Q
What is known as the master gland
A
Pituitary (hypophysis)
2
Q
Post and Ant pituitary other names
A
Post: Neurohypophysis, Pars Nervosa
Ant: Adenohypophysis, Pars Distalsis
3
Q
Ant. Pit hormones
A
ACTH
TSH
LH
FSH
GH
Prolactin
4
Q
Post. Pit hormones
A
Vasopressin/ADH
Oxytocin
5
Q
What are the 5 hypothalamic-anterior pituitary-end organ axes?
A
Hypothalamic-Pituitary-Growth hormone axis
Hypothalamic-Pituitary-Prolactin axis
Hypothalamic-Pituitary-Adrenal axis (HPA)
Hypothalamic-Pituitary-Thyroid axis (HPT)
Hypothalamic-Pituitary-Gonadal axis (HPG)
6
Q
Long feedback loop
A
Target hormone feeds back on the pituitary, hypothalamus, and/or CNS to regulate axis.
7
Q
Short feedback loop
A
Anterior pituitary hormone feeds back on the hypothalamus to regulate the axis.
8
Q
Very short feedback loop
A
Anterior pituitary hormone feeds back on the pituitary to regulate the axis.
9
Q
Hormones
A
Chemical messengers that are produced and secreted by one cell and act on another cell via interaction with a receptor.
10
Q
Median eminence
A
Located at the base of hypothalamus.
Highly vascularized neural tissue.
Interface between neural and peripheral endocrine systems.
11
Q
How do hypothalamic releasing hormones secreted from neurons into the median eminence, regulate hormone secretion from endocrine cells of the anterior pituitary?
A
Via the hypothalamic-hypophyseal portal vascular system.
12
Q
Relationship between hypothalamus, pituitary, and vascular system
A
Ant. pituitary receives portal venous inflow from the median eminence.
Posterior pituitary receives arterial blood via inferior hypophyseal artery.
13
Q
Secretion of releasing hormones into the primary plexus.
A
- Releasing hormones into median eminence from hypothalamic neurons.
- Travel down portal vessel to anterior pituitary.
- Act on endocrine cells of the ant. pituitary.
RH from Hypothalamic nuclei -> ME (Primary plexus) -> Pituitary stalk (Portal vessels) -> Anterior pituitary (Secondary plexus).
14
Q
What type of capillaries are present in the primary and secondary plexuses?
A
Fenestrated to allow large molecule transit.
15
Q
Neural control of Releasing Hormone secretion
A
External/Internal signal -> CNS:
Primary signal for release of RH.
May be additional interneuron that regulates release of RH at nerve ending.
RH enters blood via fenestrations.
Interneuron regulates vascular tone and blood flow to anterior pituitary (regulates hormone flow in blood).
16
Q
Hypothalamic Releasing Hormones
A
Stimulating:
Growth Hormone Releasing Hormone GHRH
Thyrotropin Releasing Hormone TRH
Corticotropin Releasing Hormone CRH
Gonadotropin Releasing Hormone GnRH
Inhibiting:
Somatostatin
Dopamine
17
Q
What are the 2 types of endocrine receptors?
A
Cell surface receptors
Intracellular receptors
18
Q
What types of receptors do ALL hypothalamic releasing hormones bind to?
A
Extracellular (cell surface) receptors = G-protein Coupled Receptors
Bulky peptides can’t cross cell membrane.
19
Q
GHRH:
1. Site of action
2. Target cell
3. Hormone influenced
4. End organ and function at end organ
A
- Anterior pituitary
- Somatotroph
- Stimulates GH release
- Multiple organs;
stimulates IGF1 production,
stimulates bone growth
protein synthesis
lipid/carbohydrate metabolism
20
Q
TRH:
1. Site of action
2. Target cell
3. Hormone influenced
4. End organ and function at end organ
5. Type of feedback loop(s)
A
- Anterior pituitary
Thyrotroph -> Stimulates TSH release
Lactotroph -> Stimulates Prolactin release - Thyroid;
stimulates production and secretion of T3 & T4
thyroid growth - Long
21
Q
CRH:
1. Site of action
2. Target cell
3. Hormone influenced
4. End organ and function at end organ
5. Type of feedback loop(s)
A
- Anterior pituitary
- Corticotroph
- Stimulates ACTH release
- Adrenal cortex;
stimulates production and secretion of glucocorticoids (cortisol)
stress response/homeostasis - Short, long
22
Q
GnRH:
1. Site of action
2. Target cell
3. Hormone influenced
4. End organ and function at end organ
5. Type of feedback loop(s)
A
- Anterior pituitary
- Gonadotroph
- Stimulates FSH & LH release
- FSH:
Follicular cells;
regulates production Estrogen/Progesterone, inhibin, activin
Sertoli cells;
regulates spermatogenesis
stimulates production/secretion of inhibin
LH:
Follicular cells;
regulates production of Estrogen/Progesterone
Leydig cells;
stimulates production of testosterone.
- Ultrashort, Short, Long
23
Q
Prolactin Releasing Factors
1. Site of action
2. Target cell
3. Hormone influenced
4. End organ and function at end organ
A
- Anterior pituitary
- Lactotrophs
- Stimulates Prolactin release
- Mammary gland;
stimulates lactation
testis and prostate
growth and development
immune function
24
Q
Somatostatin:
1. Site of action
2. Target cell
3. Hormone influenced
4. End organ and function at end organ
A
- Anterior pituitary
Somatotroph -> Inhibits GH release
Thyrotroph -> Inhibits TSH release
Corticotroph -> Inhibits ACTH release - Multiple organs
25
Dopamine:
1. Site of action
2. Target cell
3. Hormone influenced
4. End organ and function at end organ
5. Type of feedback loop(s)
1. Anterior pituitary
2. Lactotroph
3. Inhibits Prolactin release.
4. Mammary gland, inhibits milk production
5. Ultrashort, short.
26
Discuss imaging of the cavernous sinus
Included on all imaging exams of head but resolution not good enough for dx.
Dedicated imaging required.
Need a close up view to look for pathologies.
Only one component of the work up - need to understand clinical symptoms and hormone profiles.
27
Main modality for imaging the cavernous sinus
MRI
Some pathologies (large masses) may be visible on CT
28
Discuss the anatomy of the cavernous sinus
Dural venous sinus.
Divided by numerous fibrous septs into a series of small caves.
Located on either side of the pituitary fossa and body of the sphenoid.
Between endosteal and meningeal layers of the dura.
Spans from apex of orbit to apex of petrous of temporal bone.
29
MRI sequences T1/T2
T1: CSF is black
T2: CSF is white
T2 -> H2O
30
What type of MRI sequence is used for the pituitary?
T1-weighted.
With and Without IV contrast.
31
Pituitary adenoma
Most common sellar/suprasellar mass in adults.
Greater than 10mm -> vision changes, cranial neuropathies.
Glows slowly, remodelling sella turcica.
Figure 8 appearance
Macro/Micro adenomas:
Macro -> mass effect
Micro -> hormone imbalances
32
Pituitary apoplexy
Acute clinical syndrome:
headache
visual defects
altered mental status
variable endocrine deficiencies
Caused by hemorrhage or infarction of pituitary gland.
Preexisting pituitary macroadenoma common.
May present as benign event or permanent neuro defects/death.
33
What is the main signal for prolactin secretion?
Removal of dopamine (inhibitory).
34
What inhibits GnRH
Prolactin:
leads to persistence of anovulation,
hypogonadism
35
Why are TSH levels high in primary hypothyroidism?
The feedback mechanism is only a long feedback loop so TRH and tSH are not suppressed by high TSH levels.
36
In addition to the HPA axis, what other HP-axis can be tested with insulin administration?
HP-Growth hormone axis.
Growth hormone increases blood glucose in response to low glucose levels.
Insulin stimulation will increase GH levels from ant. pituitary.
37
What type of receptors does testosterone bind?
Androgen receptor which is a Nuclear receptors (intracellular).
38
What are the key effects of testosterone binding to androgen receptor?
Androgenic and anabolic effects.
39
Physiological effects of testosterone
Development of external and internal genitalia.
Maturation of sex organs.
Secondary male sex traits.
Sermatogenesis.
Sexual function.
Maintenance of bone density/linear bone growth.
Muscle development and growth, nitrogen retention.
Maintenance of normal red cell mass/hemoglobin.
Cognitive effects.
40
Clinical symptoms of low testosterone
Sexual dysfunction.
Loss of secondary sex traits (hair growth).
Decrease in hemoglobin/hematocrit.
Lower bone density.
Lower mm mass/weakness.
Increase fat mass (central obesity).
Metabolic disruption - insulin resistance, metabolic syndrome.
Low mood, motivation, vigor.
41
Why order LH and FSH levels if there is low serum testosterone?
Determine cause of hypogonadism.
42
3 endocrine rhythms
Circadian (Diurnal): 24 hr
Ultradian (Pulsatile): <24 hr
Infradian: >24 hr
Most are Circadian
43
Why are random measures of serum ACTH or cortisol not helpful in determining conditions of glucocorticoid excess or adrenal deficiency?
ACTH and GC secretions are regulated by circadian rhythms.
GC secretions should reach nadir at midnight and peak at morning.
44
Order of loss with pituitary adenoma
Go GH
Look LH
For FSH
The TSH
Adenoma ACTH
Please Prolactin
45
ACTH deficiency
1. Clinical presentation
2. Diagnosis
3. TX
1. Nausea, vomiting, fatigue, poor appetite, weight loss, headache, orthostatic hypotension, prolonged recovery from illness.
No hyperpigmentation.
Normal K+
2. AM cortisol if >300 no further testing required. If < 80 = deficient.
Stimulation test indicated if equivocal.
Cosyntropin test = 250 ug ACTH - tells primary or secondary.
Insulin induced hypoglycemia = GOLD STANDARD.
3.Glucocorticoid replacement **NOT OPTIONAL.
46
What are common sellar mass symptoms?
Headaches
Loss of vision
47
What types of investigations are done if there are sellar mass symptoms?
Hx
eye exam
formal visual field testing
imaging
48
What is the most common type of loss of vision with a sellar mass?
Bitemporal hemianopsia
49
What are well differentiated adnohypophysial tumors now classified as?
Pituitary neuroendocrine tumors.
PitNETs.
Subtyped based on cell lineage, cell type, and other characteristics.
50
List some types of acquired pituitary-hypothalamic masses.
PitNETs (functioning/non-functioning)
Pituitary cysts
Malignant pit tumors (rare)
Mestasteses
Meningioma
Optic glioma
51
List some congenital pituitary-hypothalamic lesions.
Craniopharyngioma
Rathke cleft cyst
52
List some vascular pituitary-hypothalamic lesions.
Hemangioblastoma
Aneurysm
53
List some granulomatous pituitary-hypothalamic diseases
Neurosarcoidosis
Wegner's granulomatosis
TB
54
List some infiltrative pituitary-hypothalamic disorders
Langerhans cell histiocytosis
Lymphocytis hopophysitis
55
Difference between pituitary microadenoma and macroadenoma
Microadenoma <10 mm
Micro adenoma >=10mm
56
Discuss a structured approach to a sellar mass
1. Are there mass symptoms?
2. Is the mass causing pituitary deficiencies (hypopituitarism)?
3. Is the mass functioning?
57
Order of hormone deficiencies in hypopituitarism
Go GH
Look. LH
For FSH
The TSH
Adenoma ACTH
Please Prolactin
Red flag for not being a pituitary adenoma if NOT in this order.
58
Clinical presentation of ACTH deficiency (secondary adrenal insufficiency)
Nausea
Vomiting
Fatigue
Poor appetite
Wt loss
Headache
Orthostatic hypotension
Prolonged recovery from illness
NO huyperpigmentation
NORMAL K
Postural drop in BP on exam.
59
Diagnosis of ACTH deficiency
Symptoms -> suspicion of ACTH deficiency
Screen -> AM cortisol: >300 = no deficiency, <80 = deficient
Deficiency -> check ACTH: will be low or inappropriately normal if secondary adrenal insufficiency.
Confirmation -> Stimulation test: cosyntropin test giving 250 ug of ACTH. With chronically low ACTH, cortisol producing cells atrophy and are not able to respond to exogenous ACTH. Diagnosis Primary and Secondary ACTH.
Gold standard is Insulin Induced Hypoglycemia test: cortisol should increase >500 nmol/L
60
ACTH deficiency treatment
NOT OPTIONAL: Glucocorticoid replacement, hydrocortisone 10-25 mg/day in 2-3 divided doses.
Dose adjusted based on response - avoid over-replacement.
Educate on needing extra if ill, injectable in emergency/when not able to take oral.
Medical alert bracelet.
61
Clinical presentation of TSH deficiency
Fatigue
Cold intolerance
Constipation
Weight gain
Dry skin
62
Diagnosis of TSH deficiency
TSH low or inappropriately normal with low fT4.
TRH stimulation test rarely necessary.
63
Treatment of TSH deficiency
L-Thyroxine
Adjust dose to target normal fT4
64
Clinical presentation of gonadotropin deficiency
Decreased libido
ED
Gynecomastia
Menstrual irregularities
Skin changes
65
Diagnosis of gonadotropin deficiency
Men: LH, AM testosterone (within 2 hours of waking)
Women: Hx, FSH, Estradiol if menopausal
GnRH stimulation test rarely necessary.
66
Treatment of gonadotropin deficiency
Men: Androgen replacement, HcG if trying to conceive.
Women: Estrogen replacement, Progesterone to prevent endometrial hyperplasia, Ovulation induction if trying to conceive.
67
Clinical presentation of GH deficiency
Children - decreased growth velocity.
Decreased energy, social isolation.
Increased body fat, decreased mm mass.
Suspect if there are other pituitary deficiencies.
68
Diagnosis of GH deficiency
IGF-1 to screen.
Can be normal in adults.
Stimulation test: Insulin induced hypoglycemia, glucagon, arginine
Macimorelin - oral growth hormone secretagogue receptor agonist.
69
Treatment of GH deficiency
Optional in adults.
Daily sc injection.
Expensive, self-pay for adults.
Adjust dose to IGF-1 in mid to upper normal range.
70
Clinical presentation of prolactin deficiency
Inability to breastfeed.
71
Diagnosis of prolactin deficiency
Prolactin levels.
TRH simulation test not necessary.
72
Treatment of prolactin deficiency
None or domperidone.
73
Order of functioning pituitary adenomas
Prolactinoma 45-65%
Acromegaly 9-15%
Cushing disease 5%
TSHoma <1%
Gonadotropinoma <1%
74
Causes of hyperprolactinemia
1. Pregnancy/breastfeeding
2. Brest stimulation, chest wall lesions.
3. Primary hypothyroidism
4. Medications
5. Renal insufficiency
6. Disruption or compression of pituitary stalk
7. Prolactinoma
8. Macroprolactin
75
What is the difference between disruption or compression of pituitary stalk and a prolactinoma?
Disruption/compression of pituitary stalk = STALK EFFECT: impaired dopamine signalling. Prolactin levels <100 ug/L
Prolactinoma = overproduction of prolactin d/t functioning adenoma. Prolactin levels <250 ug/L
76
Medications for hyperprolactinemia
1. Neuroleptics: phenothiazines (haloperidol, risperidone)
2. Anti-hypertensives: methyldopa, verapamil, reserpine
3. GI Motility: maxeran, domperidone
4. Anti-depressants: MAOi, Tricyclics
5. Other: opiates
77
Discuss hyperprolactinema : hypothyroidism
Low T3/4 feeds back to hypothalamus -> increase TRH
TRH -> increase prolactin
78
Clinical presentation of hyperprolactinemia
Women:
Galactorrhea
Decreased libido
Infertility
Amenorrhea/Oligomenorrhea
Low bone mass
Men:
Galactorrhea (rare)
Decreased libido
Decreased sperm counts
Gynecomastia
ED
Low bone mass
Prolactin inhibits pulsatile gonadotropin secretion.
79
Diagnosis of hyperprolactinemia
Rule out pregnancy.
Repeat prolactin - to make sure not d/t stress, exercise, large meal.
Rule out medication effects.
Ensure no renal insufficiency/hypothyroidism.
If no explanation for persistently elevated prolactic -> image with MRI or CT sella.
80
Treatment for prolactinoma
Dopamine agonists - 1st line: Cabergoline, Bromocriptine
Surgery if no response or can't tolerate dopamine agonists.
Radiation is last resort.
81
Bromocriptine vs Cabergoline
Cabergoline is more effective, better tolerance, less side effects, 1st line for larger tumors.
82
Clinical symptoms of acromegaly
Increase ring size
Increase show size
Arthalgias
Sweating
Snoring +/- apnea
Numbness/tingling in hands
Menstrual irregularities
Galactorrhea
Headache
Vision loss
83
Clinical signs of acromegaly
HTN
Frontal bossing (prominent/protruding forehead)
Protrusion of lower jaw
Space between teeth
Acral changes (proximal limbs)
Thickened moist skin
Skin tags
CTS
Goiter
Organomegaly
Visual field defects
84
Complications associated with acromegaly
HTN
Impaired glucose tolerance/diabetes
Dyslipidemia
OSA
Colon polyps/cancer
Cardiomyopathy
Vertebral fractures
85
Diagnosis of acromegaly
IGF-1
OGTT: measure GH @ 0, 20, 60, 90,120 minutes. Normal = <0.4 ug/L. If there is a GH producing tumor will not be able to suppress GH with glucose.
86
Treatment of acromegaly
Surgery:
Transphenoidal approach used in 95% of pit tumours.
Endoscopic removal.
Remission depends of size and location of tumour.
Medical suppressive:
1. Somatostatin analogues: octreotide, lanreotide, pasireotide
2. Dopamine agonists: Cabergoline
3. GH receptor antagonist: pegmisomant
Radiation: last resort.
87
Cushing's disease clinical presentation
Central weight gain.
Facial fullness.
Supraclavicular fullness.
Proximal mm weakness.
Insomnia.
Thinning of skin.
Easy bruising.
Striae.
Facial plethora (swelling/redness)
Acne
Hirsutism
Irregular menses
Low libido
Psych
HTN
Diabetes
Dyslipidemia
Osteoporosis/low bone mass
88
Cushing's disease diagnosis
Symptoms -> suspicion
Screen -> 24 hour free urine cortisol (>2-3 x's normal upper limit), midnight salivary cortisol, overnight dexamethasone suppression test (low cortisol rules out Cushing's disease).
Confirm high cortisol ->
morning ACTH levels: elevated or inappropriately normal = image pituitary, if nothing then IPSS, if nothing then look for exogenous source.
89
Discuss false (+) and false (-) in 1mg Dex suppression test
False (+), no suppression:
Pseudo-Cushings, Increased CBG d/t OCP or pregnancy, low dex levels d/t poor absorption, drug interactions.
False (-), suppression:
Early Cushings syndrome, high dex levels d/t slower metabolism, renal failure, liver failure.
90
Treatment of Cushings disease
1. Pituitary surgery
2. Medical therapy: ketoconazole, metyrapone, pasireotide, cabergoline, GC receptor antagonists.
3. Radiation
4. Bilateral adrenalectomy
91
Pituitary incidentaloma
10% of people.
Need to establish biochemical and clinical diagnosis before imaging so that incidentaloma doesnt mislead you.
92
List hormones that regulate growth
GH
IGF-1, IGF-2
Insulin
Thyroid hormones
Glucocorticoids
Androgens, estrogen
93
What are the determinants of normal post-uterine growth
GH
IGF-1
94
Releasing hormone for GH
GHRH
95
Inhibiting hormone for GH
Somatostatin
96
Which cell type produces GH?
Somatotrophs
97
Target hormone for GH
IGF-1 from liver
98
Major functions of GH
1. Growth: IGF-1, growth of skeleton, mm, CT, cells in viscera.
2. Metabolic actions: counter regulatory to insulin - increases gluconeogenesis, decreases mm glucose uptake, increases lipolysis.
99
When is GH released as a counter regulatory hormone to insulin
During a prolonged fast.
Increases glucose production.
Decreases glucose utilization.
Increases lipolysis.
Prevents neuroglycopenia.
100
Characteristics of GH secretion
0.4 mg secreted per day.
High in newborns, tapers off in old age.
101
GH secretion
Pulsatile secretion.
Circadian rhythm: Peaks during early deep sleep cycles - important for growth promotion.
Sleep/wake cycle, not light/dark cycle.
Shift workers may be affected d/t sleep disturbances.
102
Regulation of GH secretion
Dual control:
Sleep, metabolic signals, excercise -> releasing or inhibiting hormones that innervate the median eminence.
103
When are surges of GH most prominent
Pubertal growth period
104
What regulates the amplitude and frequency of GH surges?
Hypothalamus.
105
Stimuli for GH secretion
Sleep: Serotonergic and cholinergic fibers stimulate GHRH neurons in the arcuate nucleus.
Orexins also interact with the HP-GH axis, inhibiting it.
Hypoglycemia: Adrenergic fibers (NE) stimulate GHRH and inhibit somatostatin. Ghrelin too.
106
Discuss feedback regulation of GH secretion
Very-short feedback: GH -> pituitary
Short feedback: GH -> hypothalamus
Long feedback: IGF-1 -> hypothalamus
107
Discuss GH binding protein
40% of circulating GH bound to high affinity glycoprotein (acts as reservoir).
Protein is soluble form of extracellular domain of GH receptor.
Reduces rate of GH degradation - extends 1/2 life.
108
Discuss GH receptor and activation
GH receptor is extracellular receptor.
Tyrosine-kinase associated receptor, JAK - phosphorylation cascade to upregulate gene expression to increase IGF-1
109
What mediates GH effects on growth?
IGF-1
Acts at the epiphyseal growth plate.
Causes hypertrophy and hyperplasia if chondrocytes at growth plate.
Stimulates proliferation and differentiation of osteoblasts.
Increases growth rate of bone.
Sex hormones in puberty influence IGF-1 for long bone growth, but also close the growth plate.
110
Discuss the paradox of metabolic effects of GH and IGF-1
GH opposes insulin action, increases BG levels in response to fasting.
IGF-1 has insulin like effects.
111
Gigantism
GH excess before epiphyseal fusion.
Excessive long bone growth.
Caused by pituitary hyperplasia d/t hypersecretion of GHRH.
112
Acromegaly
GH excess after puberty.
Long bones dont lengthen because epiphyseal plate already closed.
Thickening of bones and soft tissues of head, hands, feet.
Caused by pit adenoma usually.
Extra pituitary cause from pancreatic islet cell tumor.
Also GHRH excess from hypothalamic tumour or peripheral tumour.
113
GH deficiency
Can result from dysfunction at all levels of the axis resulting in short stature.
Hypothalamic dysfunction
Pituitary dysfunction
Disturbed GH action
Disturbed IGF-1 action
114
