Block 4 Lecture 1 -- Pituitary Hormones Flashcards
What are the 3 structural groups of pituitary hormones?
1) somatropes
2) glycoprotein hormones
3) POMC-derived hormones
What are the somatotropes?
1) GH
2) PRL
3) PL
Describe somatotrope structure.
single polypeptide (22kDa, 190 AA)
What are the glycoprotein hormones?
1) LH
2) FSH
3) hCG
4) TSH (thyrotropin)
What are the POMC-derived hormones?
ACTH
alpha-MSH
Describe POMC-derived hormone structure?
short polypeptides
Describe glycoprotein hormone structure
heterodimeric protein
– common a
– unique b
sugar modified
What are the hypothalamic releasing hormones?
1) GHRH
2) GnRH
3) TRH
4) CRH
5) somatostatin
Describe the GHRH receptor.
Gs, increases cAMP and Ca++ release
What endogenous substances induce GH release?
1) ghrelin
2) DA
3) 5-HT
4) Arg
5) a-adrenergic agonists
6) GHRH
What activities induce GH secretion?
1) hypoglycemia
2) stress
3) exercise
How is GHRH release stimulated?
stress
sleep
exercise
What things inhibit GH release?
1) beta-agonists
2) FFAs
3) glucose
4) IGF-1
5) GH
Where is ghrelin produced?
endocrine cells of stomach
What is the function of ghrelin?
1) suppresses SST release
2) stimulates GHRH release from HT
What things increase GH-binding protein levels?
obesity
estrogens
(decreases free GH)
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
Describe SST receptors.
family of 5 Gi GPCRs
– SSTR2, 5 most important for GH regulation
Where is SST synthesized?
brain neurons and GI neuroendocrine cells
What are the functions of GH’s circulating binding protein?
binds 25-45%
- delays GH clearance
- dampens fluctuations from pulsatile secretion
Describe GH concentration across time
- irregular pulsatile release
- undetectable between pulses
- greatest at night during sleep
– highest in children, esp. puberty
Describe the structure of GH.
2 forms, bioequivalent
– one is alternatively spliced
What is the most abundant AP hormone?
GH (40% of AP cells)
How is the ability of AP to suppress GH tested?
AP suppression test
– oral glucose
How is the ability of AP to secrete GH tested?
insulin tolerance test
- generates hypoglycemia
- GH released in 45-90 min
What are the effects of GH?
induces release of IGF-1 on target tissues
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
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
Where is the GH binding protein derived from?
GH receptor, by proteolysis
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
How is GH deficiency diagnosed in adults?
1) IGF-1 levels below age/sex-adjusted values
2) failure of provocative test
GH deficiency is associated with:
1) CV morbidity and mortality
2) hyperlipidemia
3) decreased muscle mass and bone density
What are the somatropins?
GH preps identical to human GH
- Serostim
- Genotropin
- Humatrope
What is Protropin?
modified GH
What is sermorelin acetate?
synthetic GHRH
What are “stacked” amino acids?
claims to stimulate GH
- contain Arg and L-DOPA
- no evidence of benefit in athletes as anabolic agent
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
What are ADRs of GH replacement therapy in kids?
rare usually in first 8 wks -- intracranial HTN -- visual changes -- HA -- n/v
What are contraindications for GH therapy?
tumor and leukemia patients
What are symptoms of gigantism?
long bone growth due to unfused epiphyses
What are symptoms of acromegaly?
--adults! large hands and feet arthropathy carpal tunnel visceromegaly macroglossia HTN glucose intolerance HA sleep apnea
How is gigantism diagnosed?
OGTT in GH suppression
How is acromegaly diagnosed?
usually around 40-45 yo
- acromegaly + GH or IGF-1 increase
- failure of OGTT in GH suppression
Acromegaly is associated with…
1) shortened life expectancy
2) 2-fold increase in CVD
How is GH excess treated?
- treatment of choice: transsphenoidal surgery
- radiation
- drugs, even after surgery
What are the somatostatin analogs?
octreotide (sandostatin)
What are the ADRs of octreotide?
GI in 50% of patients
- diminish over time
- nausea, diarrhea, pain
How is octreotide supplied?
1) SQ injection (duration = 12h)
2) IM monthly injection
What are the DA receptor agonists?
cabergoline (Dostinex)
What are the GH receptor antagonists?
pegvisomant (Somavert)
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
What are the ADRs of cabergoline?
nausea, lightheadedness
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
How is pegvisomant monitored?
1) dose titrated on serum IGF-1
2) liver enzymes: hepatotoxic
How is pegvisomant supplied?
SQ injection
Describe the structure of prolactin
related to GH
- 23 kDa, 199 AA
- 3 Cys-disulfides
- some is glycosylated
How is prolactin secretion induced?
1) sleep
2) stress
3) hypoglycemia
4) exercise
5) estrogen
6) breast suckling
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
How is prolactin secreted?
pulsatile
– cyclic in females; constant in males
in fetus, secreted by pituitary until bith
How is prolactin secretion regulated?
- mainly by DA (inhibitory)
- - TRH can induce secretion in severe hypothyroidism
What are symptoms of hyperprolactinemia?
women: -- galactorrhea -- amenorrhea -- infertility men: -- impotence -- loss of libido -- infertility
How is hyperprolactinemia treated?
surgery is preferred
D2 receptor agonists
What are the D2 receptor agonists?
1) bromocriptine (Parlodel)
2) cabergoline (Dostinex)
3) quinagolide
4) pergolide (Permax)
What are the effects of D2 receptor agonist therapy?
1) reduce symptoms
2) reduce tumor size
3) regain fertility, become pregnant
What are the ADRs of bromocriptine?
tolerance developed over time
- n/v (common)
- HA; occasional CNS effects
- postural hypotension
How does cabergoline compare to bromocriptine?
1) 4x affinity
2) slightly more effective
3) less nausea
half-life is 65h (compared to 8h)
When is quinagolide used?
only in Europe
When is pergolide used?
(?)
it’s the cheapest
off-label (normally for PD)
Describe PK of bromocriptine.
absorption good
rapid first-pass
t1/2 = 2-8 h
What D2 agonist is preferred in patients trying to get pregnant?
bromocriptine
Describe the structure of GnRH.
decapeptide from 92-aa precursor
How is GnRH supplied clinically?
1) Gonadorelin
2) Factrel
How are GnRH analogs supplied?
1) leuprolide
2) buserelin
3) nafarelin
How are GnRH antagonists supplied?
1) cetrorelix
2) ganirelix
3) abarelix
What GnRH depot (3-month) preparations are available?
1) goserelin (Zoladex)
2) triptorelin (Trelstar LA)
How is GnRH used?
for differentiation of hypothalamic vs. pituitary defects
- SQ or IV
- monitor LH
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)
How do GnRH analogs compare to GnRH?
- longer t1/2
- - higher affinity for receptor than GnRH
What are GnRH antagonists used for?
symptomatic tx of hormonally-responsive tumors (prostate, breast)
Describe the structure of oxytocin
cyclic nonapeptide related to vasopressin
Where is oxytocin secreted?
1) posterior pituitary
2) ovarian luteal cells
3) endometrium
4) placenta
What factors stimulate oxytocin release?
- pain, dehydration, hemorrhage/hypovolemia
- estrogen
- cervicovaginal dilation (stage ii of labor)
What factors inhibit oxytocin release?
- EtOH
- - relaxin
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
For what is oxytocin used?
1) induction/augmentation of labor
2) to prevent hemorrhage post-delivery (uterine contraction)
What should be monitored when oxytocin is given?
1) fetal HR
- - prevent hyperstimulation, uterine tetany
2) fluid intake
- - beware water intoxication (antidiuretic effect)
What’s the t1/2 of oxytocin?
3 minutes
What are the psychosocial roles of oxytocin?
1) contentment, anxiolytic, calmness, security
2) trust, generosity
3) mother-infant bonding
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
Oxytocin levels are associated with:
1) mother-infant mutual gaze
2) human-dog mutual gaze/petting
3) orgasm
4) romantic attachment
Describe the structure of vasopressin.
cyclic nonapeptide related to oxytocin
- 2 aa difference
- cleaved from pre-prohormone synthesized in HT
What factors induce vasopressin secretion?
1) increased plasma osmolarity
2) severe hypovolemia/hypotension
3) AngII
4) TCAs, lithium, nicotine, morphine, ethanol, glucocorticoids
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
What are the effects of the V1a, V1b receptors?
vasoconstriction
What are the effects of the V2 receptor?
1) insertion of preformed aquaporin-2s into apical (luminal) membrane
2) increased sodium recovery
What is the MoA for DDAVP?
selective V2 receptor agonist
– 3000x higher affinity
eliminates pressor effect at therapeutic dose
Describe the structure of DDAVP.
AVP, but..
- D-Arg subbed for Arg at 8
- deaminated N-terminus
ADRs of DDAVP.
1) mild facial flushing
2) HA
3) allergic rxn
4) nasal congestion/rhinorrhea
caution: water intoxication
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
For what is DDAVP used?
1) central DI
2) some forms of von Willebrand’s disease
What is von Willebrands disease?
clotting factor defect
DDAVP increases the vW-factor
What are causes of central DI?
inadequate AVP secretion due to…
- familial
- injury
- HT-pituitary tumor
What are signs & symptoms of DI?
1) excessive urine production
2) polydipsia
3) dilute urine (less than 200 mOsm/L)
What is the pathology of nephrogenic DI and what are its forms?
inadequate AVP response
- congenital form
- acquired form
What causes acquired nephrogenic DI?
lithium is most common
- interferes with V2-mediated activation of adenylate cyclase
- reversible
What causes congenital nephrogenic DI?
defective X-linked V2 receptors
or, defective aquaporin-2 channels
How is nephrogenic DI treated?
not with DDAVP!!
- -thiazides
- -NSAIDs
–amiloride if lithium-induced
How is central DI treated?
1st line) DDAVP
2nd line) chlorpropamide
– only when DDAVP not tolerated
adjuncts:
- thiazides: added to chlorpropamide
- NSAIDs (indomethacin)
What is the MoA of chlorpropamide?
oral sulfonylurea
– potentiates AVP (AVP is required!)
What is the MoA of thiazide diuretics?
promotes water recovery prior to collecting ducts
– enhanced by dietary sodium restriction
What is the MoA of amiloride?
Na-channel blocker
- blocks reuptake of lithium
- reverses lithium-induced DI
What are ADRs of amiloride?
GI upset, n/v
What is the MoA of indomethacin when used for DI?
NSAID
- decreases GFR
- blocks PGs in juxtaglomerular apparatus
Why is abarelix not used?
hypersensitivity reaction issue
– limited distribution
What are treatment considerations for endometriosis and acute intermittent porphyria with GnRH analogs?
limit to 6 months!
Why might GnRH analogs be useful in infertility?
available via a pump to stimulate ovulation
- lower risk of multiple pregnancy
- easy to measure
Describe the secretion of GnRH across life?
pulsatile
- begins as fetus; diminishes after 1 year
- greater amplitude and frequency in puberty
Describe GnRH receptor
Gq GPCR
- -increases Ca
- stimulates release of FSH and LH
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
What are causes of hyperprolactinemia?
relatively common
- usually PRL-secreting adenomas
- HT/pituitary disease
- hypothyroidism (hi TRH)
- DAr antagonists
What are the effects of octreotide use?
decreases pituitary tumor size
inhibits TSH secretion
What are the effects of GH use in adults?
– increased bone and muscle mass
does NOT slow aging or improve strength in the elderly
Why don’t GH therapy patients continue treatment after puberty?
provocative tests show that GH secretion is gained as adults
How does sermorelin acetate compare to somatropins?
- less expensive
- less effective
- not effective in AP disease (adults)
How is sermorelin acetate monitored?
GH levels
How is protropin treatment monitored?
IGF-1 (response, and compliance)
stop treatment when bone epiphyses close
What is the presumption when GH deficiency is found in adults vs. children?
adults: AP disease
children: HT defect
What impact did rGH have on GH therapy?
increased utilization
– eliminated risk of Creutzfeldt-Jakob disease from cadaver pituitaries
GH deficiency causes:
proportionate dwarfism
What is achondroplasia?
normal body size, but shortened limbs
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
Pituitary hormones regulate…
1) growth/development
2) metabolism
3) reproduction
4) stress response
Name the 7 dwarfs:
1) Doc
2) Grumpy
3) Happy
4) Sleepy
5) Bashful
6) Sneezy
7) Dopey
