Block 4 Lecture 1 -- Pituitary Hormones Flashcards Preview

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Flashcards in Block 4 Lecture 1 -- Pituitary Hormones Deck (133):
1

What are the 3 structural groups of pituitary hormones?

1) somatropes
2) glycoprotein hormones
3) POMC-derived hormones

2

What are the somatotropes?

1) GH
2) PRL
3) PL

3

Describe somatotrope structure.

single polypeptide (22kDa, 190 AA)

4

What are the glycoprotein hormones?

1) LH
2) FSH
3) hCG
4) TSH (thyrotropin)

5

What are the POMC-derived hormones?

ACTH
alpha-MSH

6

Describe POMC-derived hormone structure?

short polypeptides

7

Describe glycoprotein hormone structure

heterodimeric protein
-- common a
-- unique b
sugar modified

8

What are the hypothalamic releasing hormones?

1) GHRH
2) GnRH
3) TRH
4) CRH
5) somatostatin

9

Describe the GHRH receptor.

Gs, increases cAMP and Ca++ release

10

What endogenous substances induce GH release?

1) ghrelin
2) DA
3) 5-HT
4) Arg
5) a-adrenergic agonists
6) GHRH

11

What activities induce GH secretion?

1) hypoglycemia
2) stress
3) exercise

12

How is GHRH release stimulated?

stress
sleep
exercise

13

What things inhibit GH release?

1) beta-agonists
2) FFAs
3) glucose
4) IGF-1
5) GH

14

Where is ghrelin produced?

endocrine cells of stomach

15

What is the function of ghrelin?

1) suppresses SST release
2) stimulates GHRH release from HT

16

What things increase GH-binding protein levels?

obesity
estrogens

(decreases free GH)

17

Describe the structure of SST.

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

Describe SST receptors.

family of 5 Gi GPCRs
-- SSTR2, 5 most important for GH regulation

19

Where is SST synthesized?

brain neurons and GI neuroendocrine cells

20

What are the functions of GH's circulating binding protein?

binds 25-45%
-- delays GH clearance
-- dampens fluctuations from pulsatile secretion

21

Describe GH concentration across time

-- irregular pulsatile release
-- undetectable between pulses
-- greatest at night during sleep

-- highest in children, esp. puberty

22

Describe the structure of GH.

2 forms, bioequivalent
-- one is alternatively spliced

23

What is the most abundant AP hormone?

GH (40% of AP cells)

24

How is the ability of AP to suppress GH tested?

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