Block 4 Lecture 1 -- Pituitary Hormones Flashcards
1
Q
What are the 3 structural groups of pituitary hormones?
A
1) somatropes
2) glycoprotein hormones
3) POMC-derived hormones
2
Q
What are the somatotropes?
A
1) GH
2) PRL
3) PL
3
Q
Describe somatotrope structure.
A
single polypeptide (22kDa, 190 AA)
4
Q
What are the glycoprotein hormones?
A
1) LH
2) FSH
3) hCG
4) TSH (thyrotropin)
5
Q
What are the POMC-derived hormones?
A
ACTH
alpha-MSH
6
Q
Describe POMC-derived hormone structure?
A
short polypeptides
7
Q
Describe glycoprotein hormone structure
A
heterodimeric protein
– common a
– unique b
sugar modified
8
Q
What are the hypothalamic releasing hormones?
A
1) GHRH
2) GnRH
3) TRH
4) CRH
5) somatostatin
9
Q
Describe the GHRH receptor.
A
Gs, increases cAMP and Ca++ release
10
Q
What endogenous substances induce GH release?
A
1) ghrelin
2) DA
3) 5-HT
4) Arg
5) a-adrenergic agonists
6) GHRH
11
Q
What activities induce GH secretion?
A
1) hypoglycemia
2) stress
3) exercise
12
Q
How is GHRH release stimulated?
A
stress
sleep
exercise
13
Q
What things inhibit GH release?
A
1) beta-agonists
2) FFAs
3) glucose
4) IGF-1
5) GH
14
Q
Where is ghrelin produced?
A
endocrine cells of stomach
15
Q
What is the function of ghrelin?
A
1) suppresses SST release
2) stimulates GHRH release from HT
16
Q
What things increase GH-binding protein levels?
A
obesity
estrogens
(decreases free GH)
17
Q
Describe the structure of SST.
A
SST-14 or SST-28
– proteolysis of precursor peptide
core is a 12-aa cyclic peptide formed by disulfide Cys-Cys
- 4 aa sequence is essential to receptor binding
- Phe-Trp-Lys-Thr
18
Q
Describe SST receptors.
A
family of 5 Gi GPCRs
– SSTR2, 5 most important for GH regulation
19
Q
Where is SST synthesized?
A
brain neurons and GI neuroendocrine cells
20
Q
What are the functions of GH’s circulating binding protein?
A
binds 25-45%
- delays GH clearance
- dampens fluctuations from pulsatile secretion
21
Q
Describe GH concentration across time
A
- irregular pulsatile release
- undetectable between pulses
- greatest at night during sleep
– highest in children, esp. puberty
22
Q
Describe the structure of GH.
A
2 forms, bioequivalent
– one is alternatively spliced
23
Q
What is the most abundant AP hormone?
A
GH (40% of AP cells)
24
Q
How is the ability of AP to suppress GH tested?
A
AP suppression test
– oral glucose
25
How is the ability of AP to secrete GH tested?
insulin tolerance test
- - generates hypoglycemia
- - GH released in 45-90 min
26
What are the effects of GH?
induces release of IGF-1 on target tissues
27
Where are the target sites of GH / where is IGF-1 produces?
liver, bone, adipose, muscle
- - liver is primary source of IGF-1
- - peripheral IGF-1 production is essential to growth
28
What are the effects of IGF-1?
causes anabolic and growth effects
| -- acts on secondary tissues thru IGF-1 receptor, which is on most cells
29
Where is the GH binding protein derived from?
GH receptor, by proteolysis
30
How is GH deficiency diagnosed in kids?
1) short stature/slow growth
2) delayed bone age
3) provocative test showing GH less than 10 ng/mL
31
How is GH deficiency diagnosed in adults?
1) IGF-1 levels below age/sex-adjusted values
| 2) failure of provocative test
32
GH deficiency is associated with:
1) CV morbidity and mortality
2) hyperlipidemia
3) decreased muscle mass and bone density
33
What are the somatropins?
GH preps identical to human GH
- - Serostim
- - Genotropin
- - Humatrope
34
What is Protropin?
modified GH
35
What is sermorelin acetate?
synthetic GHRH
36
What are "stacked" amino acids?
claims to stimulate GH
- - contain Arg and L-DOPA
- - no evidence of benefit in athletes as anabolic agent
37
What are GH replacement therapy ADRs in adults?
```
dose-related
most common in older/obese patients
1) peripheral edema
2) carpal tunnel
3) arthralgia
4) myalgia
```
38
What are ADRs of GH replacement therapy in kids?
```
rare
usually in first 8 wks
-- intracranial HTN
-- visual changes
-- HA
-- n/v
```
39
What are contraindications for GH therapy?
tumor and leukemia patients
40
What are symptoms of gigantism?
long bone growth due to unfused epiphyses
41
What are symptoms of acromegaly?
```
--adults!
large hands and feet
arthropathy
carpal tunnel
visceromegaly
macroglossia
HTN
glucose intolerance
HA
sleep apnea
```
42
How is gigantism diagnosed?
OGTT in GH suppression
43
How is acromegaly diagnosed?
usually around 40-45 yo
- - acromegaly + GH or IGF-1 increase
- - failure of OGTT in GH suppression
44
Acromegaly is associated with...
1) shortened life expectancy
| 2) 2-fold increase in CVD
45
How is GH excess treated?
- - treatment of choice: transsphenoidal surgery
- - radiation
- - drugs, even after surgery
46
What are the somatostatin analogs?
octreotide (sandostatin)
47
What are the ADRs of octreotide?
GI in 50% of patients
- - diminish over time
- - nausea, diarrhea, pain
48
How is octreotide supplied?
1) SQ injection (duration = 12h)
| 2) IM monthly injection
49
What are the DA receptor agonists?
cabergoline (Dostinex)
50
What are the GH receptor antagonists?
pegvisomant (Somavert)
51
When is cabergoline used for GH excess?
acromegaly
- - best with tumors secreting PRL + GH
- - can be used with somatostatins
- - useful when patient refuses SST injection
52
What are the ADRs of cabergoline?
nausea, lightheadedness
53
What is the MoA of cabergoline in GH excess?
decreases GH secretion in some patients
-- (increases secretion in normal patients)
much higher dose than hyper-PRL-emia
54
How is pegvisomant monitored?
1) dose titrated on serum IGF-1
| 2) liver enzymes: hepatotoxic
55
How is pegvisomant supplied?
SQ injection
56
Describe the structure of prolactin
related to GH
- - 23 kDa, 199 AA
- - 3 Cys-disulfides
- - some is glycosylated
57
How is prolactin secretion induced?
1) sleep
2) stress
3) hypoglycemia
4) exercise
5) estrogen
6) breast suckling
58
What are the effects of prolactin?
acts on PRL receptor to...
- - prepare for milk production and secretion
- - suppress GnRH (infertility)
PRL receptor are on many tissues; functions unknown
59
How is prolactin secreted?
pulsatile
-- cyclic in females; constant in males
in fetus, secreted by pituitary until bith
60
How is prolactin secretion regulated?
- - mainly by DA (inhibitory)
| - - TRH can induce secretion in severe hypothyroidism
61
What are symptoms of hyperprolactinemia?
```
women:
-- galactorrhea
-- amenorrhea
-- infertility
men:
-- impotence
-- loss of libido
-- infertility
```
62
How is hyperprolactinemia treated?
surgery is preferred
| D2 receptor agonists
63
What are the D2 receptor agonists?
1) bromocriptine (Parlodel)
2) cabergoline (Dostinex)
3) quinagolide
4) pergolide (Permax)
64
What are the effects of D2 receptor agonist therapy?
1) reduce symptoms
2) reduce tumor size
3) regain fertility, become pregnant
65
What are the ADRs of bromocriptine?
tolerance developed over time
- - n/v (common)
- - HA; occasional CNS effects
- - postural hypotension
66
How does cabergoline compare to bromocriptine?
1) 4x affinity
2) slightly more effective
3) less nausea
half-life is 65h (compared to 8h)
67
When is quinagolide used?
only in Europe
68
When is pergolide used?
(?)
it's the cheapest
off-label (normally for PD)
69
Describe PK of bromocriptine.
absorption good
rapid first-pass
t1/2 = 2-8 h
70
What D2 agonist is preferred in patients trying to get pregnant?
bromocriptine
71
Describe the structure of GnRH.
decapeptide from 92-aa precursor
72
How is GnRH supplied clinically?
1) Gonadorelin
| 2) Factrel
73
How are GnRH analogs supplied?
1) leuprolide
2) buserelin
3) nafarelin
74
How are GnRH antagonists supplied?
1) cetrorelix
2) ganirelix
3) abarelix
75
What GnRH depot (3-month) preparations are available?
1) goserelin (Zoladex)
| 2) triptorelin (Trelstar LA)
76
How is GnRH used?
for differentiation of hypothalamic vs. pituitary defects
- - SQ or IV
- - monitor LH
77
What are the indications for GnRH analogs?
1) pharmacological castration
2) precocious puberty
3) endometriosis and acute intermittent porphyria
4) infertility (not in the US)
78
How do GnRH analogs compare to GnRH?
- - longer t1/2
| - - higher affinity for receptor than GnRH
79
What are GnRH antagonists used for?
symptomatic tx of hormonally-responsive tumors (prostate, breast)
80
Describe the structure of oxytocin
cyclic nonapeptide related to vasopressin
81
Where is oxytocin secreted?
1) posterior pituitary
2) ovarian luteal cells
3) endometrium
4) placenta
82
What factors stimulate oxytocin release?
- - pain, dehydration, hemorrhage/hypovolemia
- - estrogen
- - cervicovaginal dilation (stage ii of labor)
83
What factors inhibit oxytocin release?
- - EtOH
| - - relaxin
84
What are the effects of oxytocin?
1) breast, uterine muscle contraction
2) bind vasopressin receptors at pharmacological doses
3) increases force/frequency of uterine contractions during delivery
85
For what is oxytocin used?
1) induction/augmentation of labor
| 2) to prevent hemorrhage post-delivery (uterine contraction)
86
What should be monitored when oxytocin is given?
1) fetal HR
- - prevent hyperstimulation, uterine tetany
2) fluid intake
- - beware water intoxication (antidiuretic effect)
87
What's the t1/2 of oxytocin?
3 minutes
88
What are the psychosocial roles of oxytocin?
1) contentment, anxiolytic, calmness, security
2) trust, generosity
3) mother-infant bonding
89
What additional effects are given by IN oxytocin?
possibly inhibits amygdala
-- reduced fear
-- empathy and improved facial memory (esp happy) in healthy males
may reduce caloric intake in men
90
Oxytocin levels are associated with:
1) mother-infant mutual gaze
2) human-dog mutual gaze/petting
3) orgasm
4) romantic attachment
91
Describe the structure of vasopressin.
cyclic nonapeptide related to oxytocin
- - 2 aa difference
- - cleaved from pre-prohormone synthesized in HT
92
What factors induce vasopressin secretion?
1) increased plasma osmolarity
2) severe hypovolemia/hypotension
3) AngII
4) TCAs, lithium, nicotine, morphine, ethanol, glucocorticoids
93
What are the vasopressin receptors and where are they located?
GPCRs
1) V1a, V1b (Gq, Ca)
- - widespread in vasculature
2) V2 (Gs, phosphorylation)
- - distal tubule and collecting duct
94
What are the effects of the V1a, V1b receptors?
vasoconstriction
95
What are the effects of the V2 receptor?
1) insertion of preformed aquaporin-2s into apical (luminal) membrane
2) increased sodium recovery
96
What is the MoA for DDAVP?
selective V2 receptor agonist
-- 3000x higher affinity
eliminates pressor effect at therapeutic dose
97
Describe the structure of DDAVP.
AVP, but..
- - D-Arg subbed for Arg at 8
- - deaminated N-terminus
98
ADRs of DDAVP.
1) mild facial flushing
2) HA
3) allergic rxn
4) nasal congestion/rhinorrhea
caution: water intoxication
99
How is DDAVP given?
IN or SQ 2-3 x/day
-- nasal lasts 6-12h
po form, but $$ and hi-dose due to peptide degradation
100
For what is DDAVP used?
1) central DI
| 2) some forms of von Willebrand's disease
101
What is von Willebrands disease?
clotting factor defect
| DDAVP increases the vW-factor
102
What are causes of central DI?
inadequate AVP secretion due to...
- - familial
- - injury
- - HT-pituitary tumor
103
What are signs & symptoms of DI?
1) excessive urine production
2) polydipsia
3) dilute urine (less than 200 mOsm/L)
104
What is the pathology of nephrogenic DI and what are its forms?
inadequate AVP response
- - congenital form
- - acquired form
105
What causes acquired nephrogenic DI?
lithium is most common
- - interferes with V2-mediated activation of adenylate cyclase
- - reversible
106
What causes congenital nephrogenic DI?
defective X-linked V2 receptors
| or, defective aquaporin-2 channels
107
How is nephrogenic DI treated?
not with DDAVP!!
- -thiazides
- -NSAIDs
--amiloride if lithium-induced
108
How is central DI treated?
1st line) DDAVP
2nd line) chlorpropamide
-- only when DDAVP not tolerated
adjuncts:
- - thiazides: added to chlorpropamide
- - NSAIDs (indomethacin)
109
What is the MoA of chlorpropamide?
oral sulfonylurea
| -- potentiates AVP (AVP is required!)
110
What is the MoA of thiazide diuretics?
promotes water recovery prior to collecting ducts
| -- enhanced by dietary sodium restriction
111
What is the MoA of amiloride?
Na-channel blocker
- - blocks reuptake of lithium
- - reverses lithium-induced DI
112
What are ADRs of amiloride?
GI upset, n/v
113
What is the MoA of indomethacin when used for DI?
NSAID
- - decreases GFR
- - blocks PGs in juxtaglomerular apparatus
114
Why is abarelix not used?
hypersensitivity reaction issue
| -- limited distribution
115
What are treatment considerations for endometriosis and acute intermittent porphyria with GnRH analogs?
limit to 6 months!
116
Why might GnRH analogs be useful in infertility?
available via a pump to stimulate ovulation
- - lower risk of multiple pregnancy
- - easy to measure
117
Describe the secretion of GnRH across life?
pulsatile
- - begins as fetus; diminishes after 1 year
- - greater amplitude and frequency in puberty
118
Describe GnRH receptor
Gq GPCR
- -increases Ca
- - stimulates release of FSH and LH
119
Describe feedback inhibition of GnRH secretion.
- - hypothalamic inhibition by gonadal steroids (E/P/T)
- - AP inhibitions of LH/FSH by gonadal steroids
-- T may act, by conversion to E
120
What are causes of hyperprolactinemia?
relatively common
- - usually PRL-secreting adenomas
- - HT/pituitary disease
- - hypothyroidism (hi TRH)
- - DAr antagonists
121
What are the effects of octreotide use?
decreases pituitary tumor size
| inhibits TSH secretion
122
What are the effects of GH use in adults?
-- increased bone and muscle mass
does NOT slow aging or improve strength in the elderly
123
Why don't GH therapy patients continue treatment after puberty?
provocative tests show that GH secretion is gained as adults
124
How does sermorelin acetate compare to somatropins?
- less expensive
- less effective
- not effective in AP disease (adults)
125
How is sermorelin acetate monitored?
GH levels
126
How is protropin treatment monitored?
IGF-1 (response, and compliance)
| stop treatment when bone epiphyses close
127
What is the presumption when GH deficiency is found in adults vs. children?
adults: AP disease
children: HT defect
128
What impact did rGH have on GH therapy?
increased utilization
| -- eliminated risk of Creutzfeldt-Jakob disease from cadaver pituitaries
129
GH deficiency causes:
proportionate dwarfism
130
What is achondroplasia?
normal body size, but shortened limbs
131
What are signs/symptoms of proportionate dwarfism?
1) normal body proportions and intelligence
2) growth less than 2 in/year
- - may appear after 2-3 yo
3) younger face
4) chubby build
5) delayed or absent puberty
132
Pituitary hormones regulate...
1) growth/development
2) metabolism
3) reproduction
4) stress response
133
Name the 7 dwarfs:
1) Doc
2) Grumpy
3) Happy
4) Sleepy
5) Bashful
6) Sneezy
7) Dopey
