Pharmacology of Anterior Pituitary Hormones Flashcards
Three groups that the hormones of the anterior-pituitary can be classified into
- Somatotropic hormones (growth hormone, prolactin)
- Glycoprotein hormones (LH, FSH, TSH)
- Pro-opiomelanocortin peptides (ACTH)
Five different hormone-producing cell types that have been identified in the anterior pituitary
- Somatotroph
- Lactotroph (Mammotroph)
- Thyrotroph
- Gonadotroph
- Corticotroph-lipotroph
thyroid hypofunction
very sensitive to cold; lack of sweating; reduced rate of metabolism; poor accumulation of radioiodine by thyroid
adrenal deficiency (may result in death)
sensitivity to physical stress; increased rate of infection; frequent episodes of collapse
In children, hypopituitarism (hypopituitary dwarfism) is usually the result of
failure of pituitary to develop normally during embryonic life
Is the hypopituitary dwarf mentally retarded?
No
What can help differentiate hypopituitary dwarfism from other types of dwarfism?
the responsiveness of thyroid and adrenal glands to stimulation by trophic hormones
Important feature of acromegaly
excessive growth hormone secretion (by pituitary tumor)
Characteristic of Cushing’s syndrome
oversecretion of ACTH
Increased secretion of prolactin in women leads to
amenorrhea, galactorrhea, and infertility
Increased secretion of prolactin in men leads to
impotence
Hypersecretion of gonadotrophins can result in what in children?
can result in precocious sexual development in children
Disorders and dysfunctions of target organs such as gonads, thyroid gland, adrenal gland can lead to
the release of pituitary from the negative feedback control and results in excessive secretion of various pituitary hormones
Most abundant active agent synthesized in the anterior pituitary
Growth hormone
Stimulation of growth hormone secretion
glucose decrease, FFA decrease, aa increase (arginine); fasting; prolonged caloric deprivation; stage IV sleep; exercise; stress; insulin-induced hypoglycemia etc.
Inhibition of growth hormone secretion
somatostatin; glucose increase; FFA increase; somatomedins; growth hormone; beta-agonists; cortisol; obesity; pregnancy; old age
Growth hormones causes
proportional increase in size (growth) of almost all organs in the body; it leads to increase in weight - cell proliferation rather than hypertrophy
In hypopituitary dwarfs, administration of human growth hormones results in
proportionate growth as in normal individuals
Gonadal steroids promote
epiphysial fusion
Abnormal growth of hypopituitary dwarfs with continuous GH administration
long limbs and short trunk
Preparations of growth hormone
Somatropin; Somatrem; Nutropin Depot;
Somatropin
Humatrope; Serotism; Genotropin, Nutropin, Saizen
recombinant GH injected SC in evening; weakly antigenic; reaches peak levels 2-4 hrs after injection
Somatrem
Protropin:
recombinant methionyl-growth hormone injected SC in evening; more antigenic than somatropin
Nutropin Depot
encapsulated form of somatropin for intramuscular injection once or twice per month
Absorption, fate and excretion of growth hormone
absorbed well following adminstration; maximal concentrations achieved within 2-6 hours; removed largely by liver and kidney; half-life of clearance is 15 to 30 minutes
Describe the GH receptor
monomer with a single membrane spanning domain that lacks intrinsic tyrosine kinase activity; dimerizes upon binding growth hormone
Dimerization of GH results in
the recruitment and activation of the JAK proteins which catalyze the phosphorylation and activation of PI-3 kinase, STAT, and MAPK signaling pathways
GH induces the production of
insulin-like growth factors (IGFs) known as somatomedins in the liver
Primary source of circulating IGFs
liver
Primary mediator of the actions of growth hormone
IGF-1
Type 1 IGF receptor binds
both IGF-1 and IGF-2 with high affinity
Type II IGF receptor binds
IGF-2 specifically
Type II IGF receptor signals
the encoding of cytoplasmic proteins that act as receptor for proteins targeted to lysosomes
In plasma and other body fluids, IGFs are tightly bound to
large protein carriers, the IGF-binding proteins (IGFBPs)
Characteristics of severe growth hormone deficiency
- short stature and mild adiposity
- adiposity and hypoglycemia
- predicted adult height substantially below mean parental height
- adnormally slow growth velocity
- abnormally low plasma concentrations of IGF-1
- poor responses to provocative tests for secretion of GH
To diagnose GH deficiency:
- Exclude all other causes of poor growth
- Growth rate below 4 cm/year
- Perform provocative test
What is a provocative GH test?
Administer stimuli such as insulin-induced hypoglycemia, levodopa, apomorphine, agonists of serotonin and measure plasma growth hormone within 45-90 minutes - GH level of less than standard conc. indicates deficiency
GH replacement therapy is approved in
children with idiopathic short stature (non-hormone deficient short stature) with a height that is 2.25 deviations or more below national norm for children of same age
GH is approved for children with what condition
chronic renal failure
What does GH do in children with Prader-Willi syndrome (characterized by growth failure, low muscle tone and obesity)?
growth hormone therapy decreased body fat and increased lean body mass
Adults with growth hormone deficiency have
generalized obesity, reduced muscle mass, and reduced cardiac output
Other weird uses of growth hormone
AIDS-associated wasting and patients with short bowel syndrome dependent on TPN
Rapid growth with GH may cause
scoliosis in a few patients
Rare side effect of GH in children
intracranial hypertension, visual changes, headache and nausea
Side effects of GH in adults
peripheral edema, athralgias, carpal tunnel syndrome, myalgias, mild to moderate nausea and headache
What happens with GH treatment of critically ill patients
increases mortality
Mecasermin (Increlex)
recombinant human IGF-1
Mecasermine rinfabate (Iplex)
recombinant human IGF-1/IGFBP-3
Laron-type dwarfism
inheritable growth hormone resistant disease:
receptors for GH are few or absent; plasma level of biologically active GH high; low plasma IGF-1
IGF-1 deficient patients (Laron-type dwarfs) responds well to
Mecasermin therapy
Majority of acromegaly cases are caused by
growth-hormone secreted from pituitary tumors referred to as somatotrophinomas
In patients with non-fused ephiphysis, growth hormone excess causes
enhanced longtitudinal growth and gigantism
In adults, growth hormone excess causes
acromegaly with symptoms such as arthropathy, carpal tunnel syndrome, generalized visceromegaly, hypertension, headache, lethargy, excess perspiration and sleep apnea
Treatment of Acromegaly:
- Growth hormone secreting pituitary tumors are treated with surgery or irradiation
- If growth hormone hypersecretion persists, use somatostatin analogs, dopamine receptor agonists, growth hormone antagonists
Somatostatin analogs
- Octreotide (Sandostatin)
- Lanreotide (Somatuline)
- Vapreotide
- Pasireotide (Signifor)
Agonists of dopamine are potent inhibitors of
lactotroph function
Dopamine agonists
ergot derivative such as 2-bromo-ergocrypine (bromocriptine; Parlodel), carbegoline (Dostinex)
How can a dopamine agonist inhibit growth hormone secretion by pituitary tumor cells
if the growth hormone secreting tumor cells originate from lactotrophs (prolactin secreting pituitary cells)
Pegvisomant (Somavert)
growth hormone antagonist developed by recombinant DNA technology for the treatment of acromegaly
Prolactin is synthesized and stored in
pituitary cells called lactotrophs;
also synthesized by human placental tissue
Stimulation of prolactin release
pregnancy; estrogen; nursing; sleep; stress; low glucose; dopamine antagonists; opioids; serotonin; H2 antagonists
Inhibition of prolactin release
dopamine; somatostatin; GnRH-associated peptide; prolactin; GABA; high glucose
Describe the prolactin receptor
monomer that lacks intrinsic tyrosine kinase activity; binding of prolactin causes receptor dimerization resulting in the recruitment and activation of JAK kinases that phosphorylate JAK proteins and eventually the activation of transcription factor STAT proteins
Which hormones bind prolactin receptors
prolactin, growth hormone and placental lactogen
Half life of natural prolactin
15 - 20 minutes
Preparations for treating prolactin-deficient patients
there is currently no appropriate preparation available
Hyperprolactinemia may occur
- as a result of various drugs (antagonists of dopamine)
- due to disorders of hypothalamus or pituitary gland that interfere with the action of prolactin release inhibiting hormone
- prolactin secreting pituitary tumors
Treatment of hyperprolactinemia
- irradiation and surgical removal of tumor
2. prolactin-secreting tumors are treated with dopamine agonists
Dopamine agonists used to treat prolactin secreting tumors
quinagolide (Norprolac);
ergot derivative such as bromocriptine (Parlodel);
cabergoline (Dostinex, Cabaser)
How do dopamine agonists used to treat prolactin secreting tumors work?
They activate the dopaminergic (D2) receptors that are cupled to the inhibition of prolactin release in the normal anterior pituitary gland. This dopamine-inhibitor pathway is retained by prolactin-secreting pituitary tumor cells.
Pharmacokinetics of dopamine agonists
administered orally and circulate bound to albumin; metabolized and excreted primarily in feces (bile)
Toxicity and contraindications of dopamine agonists
- Some patients experience nausea, headache, fatigue with dopamine agonist treatment
- Nausea occurs less often with carbegoline than with bromocriptine treatment
Gonadotropic hormones
Follicle-stimulating hormone (FSH), Luteinizing hormone (LH)
Describe the structure of glycoprotein hormones of the anterior pituitary
heterodimers containing alpha and beta subunits; alpha units are identical
LH and FSH levels during the menstrual cycle
Plasma LH and FSH levels are highest near the time of ovulation; plasma LH and FSH levels are also high after menopause
Secretion of chorionic gonadotropin (CG)
CG is produced during pregnancy by fetal placenta (syncytiotrophoblaslts); enters the maternal blood and supports luteal function
Gonadotropic hormones (pituitary and placenta derived) are effective only when given by
injection (intramuscular and subQ)
Chorionic gonadotropin for injection
Pregnyl; Profasi; A.P.L.
How is chorionic gonadotropin hormone used clinically?
used to treat infertility in women (administer pregnyl after a series of treatments with menotropins)
Menotropins for injection
Menopur, Pergonal, Humegon, Repronex
Clinical use of menotropins
used to treat infertility in women; give low doses of pergonal daily for 7 to 12 days; give a high dose of CG preparation
Urofollitropin for injection
Metrodin, uFSH, Fortinex, Bravelle
Activity of CG
contains LH activity
Activity of Menotropins
contains both LH and FSH activity
Activity or Urofollitropin
contains only FSH activity
Use of Urofollitropin
exactly the same as menotropins
Recombinant human FSH preparations
follitropin-alpha (Gonal-F) and follitropin - beta (Puregon, Follistim)
Recombinant human LH preparations
rhLH; Lutropin alfa; Luveris
Recombinant human LH approved for use in
in women with LH deficiency - in combination with follitropin-alpha
Recombinant Human Chorionic Gonadotropin (rhCG)
choriogonadotropin alfa (Ovidrel)
Therapeutic uses for Gonadotropin preparations
Female infertility
In vitro fertilization
Male infertility
Diagnostic uses of gonadotropins
- Pregnancy diagnosis and prediction of ovulations
2. Diagnoses of diseases of reproductive systems in both males and females
Low levels of LH and FSH can indicate
hypogonadotropic hypogonadism
High levels of LH and FSH can indicate
gonadal failure
Menopausal gonadotropins can cause
ovarian hyperstimulation/enlargement
Secretion of TSH
produced in the pituitary thyrotroph
Regulation of TSH secretion
synthesis and secretion is stimulated by TRH; circulating thyroid hormones exert negative feedback on TSH
Preparation of TSH
Thyrogen (also known as thyrotropin alpha)
MOA of TSH preparations
Thyrogen binds to TSH receptor on normal thyroid and differentiated thyroid cancer cells and stimulates cAMP production. cAMP activates a number of steps in the thyroid hormone synthetic pathways
Uses of Thyrogen
for tests involved in (131)I uptake by residual thyroid gland (post-operative) and metastasized thyroid carcinoma
Growth Hormone Analogs
- Somatropin (Humatrope, Serotism, Genotropin, Nutropin, Saizen)
- Somatrem (Protropin)
- Nutropin Depot
- Sermorelin acetate (Geref)
- Mecasermine rinfabate (Iplex)
- Mecasermin (Increlex)
Growth Hormone Antagonists
- Lanreotide (Somatuline) - somatostatin analog
- Octreotide (generic, Sandostatin) - somatostatin analog
- Pasireotide (Signifor LAR) - somatostatin analog
- Pegvisomant (Somavert)
Thyroid stimulating hormone analog
Thyrotropin, recombinant human TSH (Thyrogen, Thyrotropin alfa)
Gonadotropin Analogs
- Menotropins [hMG] (Menopur, Pergonal, Humegon, Repronex)
- Chorionic gonadotropin for injection [hCG] (Pregnyl; Profasi; A.P.L.)
- Urofollitropin (Bravelle, Metrodin, uFSH, Fortinex)
- Follitropin-alpha (Gonal-F)
- Follitropin-beta (Puregon, Follistim)
- Lutropin alfa [rhLH] (Luveris)
- Choriogonadotropin alfa (Ovidrel)
Gonadotropin-Releasing Hormone Analogs
- Gonadorelin hydrochloride [GnRH] (Lutrepulse; Factrel)
- Leuprolide acetate (Lupron, Eligard)
- Histrelin acetate (Supprelin LA, Vantas)
- Nafarelin acetate (Synarel)
- Goserelin acetate (Zoladex)
- Triptorelin pamoate (Trelstar)
Gonadotropin-Releasing Hormone Antagonists
- Ganirelix (Antagon, Orgalutran)
- Cetrorelix (Cetrotide)
- Abarelix (Plenaxis)
- Degarelix (Fimagon)
Prolactin Antagonists (Dopamine agonists)
- Bromocriptine (Parlodel)
2. Carbegoline (Dostinex)
