Introduction to Endocrinology: The Hypothalamic-Pituitary Axis Flashcards
Anterior lobe (adenohypophysis) consists of:
Pars distalis
Pars tuberalis
Pars intermedia
Consists of pars nervosa which is connected by infundibulum
(pituitary stalk) to the median eminence (tuber cinereum) of
hypothalamus.
Posterior lobe (neurohypophysis)
Somatostatin: ____ growth hormone
Decrease
Somatostatin: _____ TSH
Decrease
Dopamine: ___ prolactin
Decrease
Thyrotropin-releasing hormone: ___ prolactin
Increase
Gonadtropin-releasing hormone: ___ FSH
Increase
Gonadtropin-releasing hormone: ___ LH
Increase
Acidophilic hormones:
Somatotropes
Mammotropes
Basophilic hormones:
Thyrotropes
Gonadotropes
Corticotropes
single polypeptide chain of 22 kDa; w/ 2 disulfide
bonds, not glycosylated
Growth hormone
Growth hormone gene resides on the long arm of __________.
chromosome 17
Most abundant ant. pituitary hormone
GH
Increased secretion in children
GH
greatest at night shortly after onset of deep sleep
GH
GH stimulus
Main GHRH and ghrelin
Minor stimulus of GH:
DA 5HT a2 receptor agonists Hypoglycemia Exercise Stress Emotional excitement Ingestion of protein-rich meals
Major peripheral effector of GH
IGF-1
GH suppressors
IGF-1 (from peripheral tissues)
Somatostatin (from hypothalamus)
GH levels (from anterior pituitary)
Stimulates longitudinal growth of bones
GH
increase bone mineral density
GH
myeloblast differentiation & increased mm mass
GH
Increases GFR
GH
preadipocytes to adipocyte differentiation
GH
GH ____ glucose utilization
Decrease
GH ____ lipolysis
Increase
Anti-insulin action
GH
Induction of insulin-like growth factor (IGF-1)
GH
Height diagnosis of GH deficiency
> 2 to 2.5 SD below normal
“provocative testing”
<10ng/ml
severe deficiency
<5 ng/mL
Human GH by recombinant DNA Technology
Somatotropin
Somatotropin dosage in children
25-50ug/kg/day SQ in the evening
Somatotropin dosage in adults
150-300 ug/d
used to monitor initial response
& compliance
Normalization of serum IGF-1 levels
Long term monitoring
Evaluation of height
Increase in growth velocity occurs w/in the ______ of therapy
first 2 yrs
Continued until closure of ________
epiphysis
Somatostatin pharmacokinetics
70% bioavailability
Once daily dosing
For adults
Normalization of GH levels
________ inhibit GH action so that a
larger dose of GH is needed to maintain the same
IGF-1 level
Estrogens (e.g., birth control medications and
estrogen supplements)
Recombinant Human IGF-1
Mecasermin
For patients with impaired growth secondary to mutations
in the GHR or postreceptor signaling pathway
Mecasermin
patients who develop antibodies against GH that interfere
with its action
Mecasermin
patients with IGF-1 gene defects that lead to primary IGF-1
deficiency
Mecasermin
Less effective than recombinant GH for impaired growth
secondary to GH deficiency or with idiopathic short
stature
Mecasermin
Dose of mecasermin
40 to 80 ug/kg SQ twice daily
Max dose of mecasermin
120 ug/kg/dose BID
Adverse effects of Mecasermin:
Hypoglycemia
Lipodystrophy
Lymphoid tissue hypertrophy
Contraindications of mecasermin:
Closed epiphysis
Active or suspected neoplasia
synthetic human GHRH
Tesamorelin
increases GH and IGF-1 levels
Tesamorelin
its clinical effects are primarily to reduce visceral fat
accumulation, with minimal effects on insulin resistance
Tesamorelin
FDA-approved for treatment of HIV-associated lipodystrophy
but not for GH deficiency
Tesamorelin
If epiphyses are unfused
Gigantism
In adults (epiphyses have fused)
Acromegaly
Gold standard of growth hormone excess
Oral glucose tolerance test
Normal response
Suppression of GH level to <1 ng/mL
fail to suppress GH level or + paradoxical increase in GH
level
acromegaly
Octreotide (Sandostatin) dosage
100 ug SQ TID
Octreotide (Sandostatin) bioavailability
100%
Octreotide (Sandostatin) peak effect
30 mins
Octreotide (Sandostatin) half life
90 mins
Octreotide (Sandostatin) Duration of action
12 hours
Octreotide (Sandostatin) LAR
10
20
30 mg
once every 4 weels
efficacy similar to Octreotide LAR
Lanreotide (Somatuline LA)
binds to multiple SST receptors; better than O and L
Pasireotide
Goal of treament of Pasireotide:
Decrease GH levels to <2.5 ng/mL after OGTT or normal IGF-1 level
more problem with glucose tolerance
Pasireotide
Somatostatin analogs
Octreotide
Lanreotide
Pasireotide
a recombinant pegylated variant of
human GH
Pegvisomant
For Acromegaly
Pegvisomant
Pegvisomant dosage
40mg SQ loading dose then 10mg/day
Not to be used in pts w/ liver dse
Pegvisomant
Lipohypertrophy at injection sites
Pegvisomant
May increase growth of GH secreting adenomas
Pegvisomant
for pts who do not respond to SST analogues or given
as adjunct
Pegvisomant
23,000-dalton protein of 199 AA w/ 3 intramolecular di-sulfide
bonds
prolactin
the synthesis and secretion starts on the _____ week of gestation.
5th
Caused by prolactin secreting pit. Adenoma (Prolactinomas)
Hyperprolactinemia
suppress prolactin
production by activation of D2 dopamine receptors: also ↓ the
size of the tumor (TOC for most patients)
Dopamine receptor agonist
Dopamine receptor agonists:
- Bromocriptine (Parlodel)
- Carbegoline (Dostinex)
- Quinagolide (Norpralac)
more potent than Bromocriptine
Carbegoline (Dostinex)
Activates D2 (Dopamine) receptors to inhibit spontaneous & TRH-induced release of prolactin
Bromocriptine (Parlodel)
Normalizes prolactin level (70 to 80%)
Bromocriptine (Parlodel)
Decrease tumor size in >50% of pts
Bromocriptine (Parlodel)
To avoid side effects of bromocriptine: Start at low dose (______) at bedtime; after
1 week increase to ____ daily: gradually increase every _______
up to ________ or until prolactin becomes normal
1.25mg
2x
3 to 7 days
5 mg 2x daily
Bromocriptine at higher concentrations:
Treatment of acromegaly and parkinsons disease
Safe to use in pregnancy
Bromocriptine
Longer half-life, higher affinity and greater selectivity to D2
receptors
Carbegoline
Preferred drug for Hyperprolactinemia (greater efficacy and lower adverse effects)
Carbegoline
Carbegoline dose:
- 25 mg 2x a week
- 5 mg once a week
May increase once every 4 weeks
Doses of ______ or less normalize PRL levels in 80% of patients
2 mg/week
At higher doses – can be used in some patients with
acromegaly alone or in conjunction with SST analogues
Carbegoline
linked to valvular heart disease at high doses
Carbegoline
______ acts on testicular Leydig cells to stimulate de novo synthesis of Androgens (primarily testosterone) from
cholesterol
LH
required for gametogenesis & for
maintenance of libido & secondary sexual characteristics
testosterone
acts on the Sertoli cells; stimulates production of proteins &
nutrients for sperm maturation
FSH
– stim. the growth of developing ovarian follicles &
induces expression of LH receptors on theca &
granulosa cells
FSH
also regulates the activity of aromatase in
granulosa cells
FSH
FSH stimulates production of ________
17 B estradiol
Precursor of ovarian 17B-estradiol
Androstenedione
required for the rupture of the dominant follicle
during ovulation & for the synthesis of progesterone by
the corpus luteum
LH
A synthetic GnRH stimulate gonadotropin release
Gonadorelin acetate (Lutrepulse)
diagnostically to differentiate between GnRH-dependent and
GnRH-independent precocious puberty
Leuprolide
As management of precocious puberty
pharmacologic castration
GnRH agonist (long acting)
Lueprolide Goserelin Histrelin Nafarelin Triptorelin
GnRH agonists treatment for endometriosis and uterine fibroids limited to _____ due to adverse effects
6 months
GnRH antagonists
Ganirelix (Antagon)
Cetrorelix (Cetrotide)
Suppress the LH surge; prevent premature follicular
luteinization in ovarian stimulation protocol
Ganirelix (Antagon)
Cetrorelix (Cetrotide)
Treatment for advanced prostate CA
Degarelix
suppresses testosterone levels to 50 ng/dL or less (i.e.,
medical castration)
Degarelix
lowers prostate-specific antigen more rapidly than GnRH
agonists without an initial testosterone surge
Degarelix
Therapeutic Uses of Gonadotropins
Male infertility
Cryptorchidism
A cyclic nonapeptide
Oxytocin
Differs from vasopressin by 2 AA
Oxytocin
stimulate the frequency & force of uterine contractions
Oxytocin
Milk ejection in breast
Oxytocin
Estrogen dependent because estrogen increases the expression of ______ receptors.
Oxytocin
Inhibitory action to oxytocin
Relaxin
_______ antagonizes the stimulant effect of oxytocin
Progesterone
CNS regulator of trust and in the autonomic NS
– linked to anxiety and fear
oxytocin
Drug of choice for induction of labor
Oxytocin (Pitocin, Syntocinon)
no sig. increase in uterine contraction;
higher rates are unlikely to be successful
If at 40mIU/min
If uterine tetany develops – stop infusion (half-life: _______)
3 minutes
Dose of ________, decrease water clearance by the
kidney
> 20mIU/min
If hypotonic fluids like _____ is infused rapidly - increased risk
of water intoxication (convulsion, coma, even death)
D5W
Augmentation of dysfunctional labor dose usually does not exceed ________.
10 mIU/min
Prevention and treatment of post-partum hemorrhage
10 iu IM or 20iu of Oxytocin in 1L of IV fluid at
10ml/min until the uterus is contracted then ↓ to 1-
2ml/min
Oxytocin antagonist
Atosiban
Tocolytic therapy for established preterm labor
Atosiban
Other Tocolytics
β adrenergic receptor agonists MgSO4 Ca2+ channel blockers COX inhibitors NO donors
Vasopressin agonist
Desmopressin
Vasopressin antagonist
Conivaptan
Oxytocin antagonist
Atosiban
Oxytocin agonist
Oxytocin
GnRH receptor antagonist
Ganirelix
GnRH receptor agonist
Leuprolide
GnRH agonist
Gonadorelin
Prolactin antagonist
Bromocriptine
GH antagonist
Octreotide
Pegvisomant
GH agonist
Somatotropin
Mecasermin
