Ph- Ant. Pituitary Agents Flashcards
What kind of drug is somatropin?
What are the indications for it’s use?
How is it delivered?
It is a recombinant hGH indicated for use with:
- GH deficiency
- Turner’s syndrome
- Noonan
- AIDS wasting
- idiopathic short stature
Dose: SQ daily injection
What kind of drug is octreotide?
What are the indications for use?
How is it delivered?
It is a long-lasting somatostatin analog indicated for use with:
- acromegaly
- carcinoid
- VIPomas
- hyperinsulinism
Dose: SQ, IM injection
What kind of drug is pegvisomant?
What are the indications?
How is it delivered?
It is a modified recombinant PEGylated GH variant that blocks GHr.
- acromegaly
Dose: SQ daily injection
What is mecasermin?
What are the indications?
How is it delivered?
It is a recombinant human IGF-1.
- IGF-1 deficiency [GHR mutation, Laron’s dwarfism, STAT5b mutation]
- GH deficiency with Ab against GH
Dose: 2x daily SQ
What 4 drugs are used to treat disorders involving growth hormone? Which increase GH? Decrease?
Increase GH:
- somatropin - hGH
- mecasermin - recomb hIGF1
Decrease GH
- Octreotide - somatostatin analog
- Pegvisomant - PEGylated GH that blocks GHr
What are the 2 drugs used to treat hyperprolactinemia?
How are they delivered?
- Bromocriptine - dopamine receptor agonist. PO daily.
2. cabergoline -dopamine receptor agonist. PO 1-2 per week [also treats acromegaly]
What are the 5 gonadotropin drugs?
- hCG
- leuprolide- synthetic GnRH agonist
- histrelin - GnRH agonist implant
- FSH
- Ganirelix - GnRH receptor ANTAGONIST
What are the thyroid related drugs?
What are the indications for use?
How is it delivered?
Thyrotropin - recombinant TSHa indicated as:
1. adjunctive diagnostic tool for thyroid cancer
Delivered by IM injection
What are the ACTH drugs?
- cosyntropin - synthetic ACTH analog
- Pasireotide - glucocorticoid receptor antagonist
- Mifepristone - glucocorticoid receptor antagonist
What % of the anterior pituitary is:
- GH
- PRL
- ACTH
- TSH
- FSH/LH
- 40-50
- 10-30 [lower for men, nulliparous women]
- 10-20
- 5
- 10-15% scattered throughout
What is the structure of GH?
Does it have direct or indirect actions?
What are the 3 main functions of GH?
It is a non-glycosylated peptide hormone that has direct actions on target tissue AND indirect actions via IGF1 [ most of the growth promoting actions].
- growth
- lipolysis
- counter-regulatory to hypoglycemia
Describe the mechanism of GH action.
- GH binds GHR
- GHR recruits Jak2 kinase
- Jak2 phosphorylates STAT5
- STAT5 promotes transcription of IGF1
A patient presents with high GH, but significant short stature and poor growth. What are 2 possible mechanism by which this occurs?
How can they be treated?
- inactivating mutations in STAT5b
- Laron’s dwarfism [mutation in GHR that inactivates it]
Achieve improved growth with administration of IGF1 [mecasermin]
What are the direct actions of GH?
GH actions oppose actions of insulin and synergize with cortisol:
- lipolysis is stimulated in adipocytes
- glucose uptake is inhibited in adipocytes
- gluconeogenesis and glucose output are stimulated in the liver
Net effect: preserve circulating glucose levels
What are the indirect actions of GH?
the indirect actions are mediated by IGF-1 from the liver. IGF-1 mediates:
- anabolic effects of GH - increase bone matrix/skeletal growth, soft tissue growth, AA uptake and protein synthesis
- lowers plasma glucose [bc it mimics proinsulin and binds insulin receptors. THIS COUNTERS DIRECT ACTION OF GH]
In what way do the direct actions of GH counter the indirect actions?
GH stimulates glucose release and gluconeogenesis [increasing serum glucose]
IGF1 is structurally similar to proinsulin and can activate the insulin receptor at high levels [decreasing serum glucose]
Why are IGF serum levels used as information about integrated levels of GH?
They have a long half life and are quite stable because they bind to IGFBP3 and ALS (acid labile subunit) to form a circulating complex .
GH is released from ant. pituitary in a pulsatile manner and so between pulses serum GH is basically zero
What are the hypothalamic positive regulator and negative regulator of GH secretion by pituitary somatotropes?
Where does each come from?
Positive regulator = GHRH produced by neurons in the arcuate nucleus
Negative regulator = SST (somatostatin) produces by neurons more widely dispersed in the hypothalamus
What cell in the ant. pituitary secrete GH?
What percent of the cells in the anterior pituitary do this?
Somatotropes make up 40% of the ant. pituitary and secrete GH
Why are random measurements of GH NOT useful for diagnosing GH deficiency [and only mildly useful for acromegaly]?
Somatotropes secrete GH in a pulsatile manner and between pulses GH is essentially zero.
This could give a false diagnosis of GH deficiency.
When are somatotrope GH pulses most frequent and of greatest magnitude?
They are most frequent and of greatest magnitude in sleep
What cell of the ant. pituitary is most susceptible to insult?
Somatotrope
What is the most common single anterior pituitary hormone deficiency?
GH deficiency
What is feedback regulation for the GH loop?
IGF1 has receptors on the hypothalamus AND pituitary gland to inhibit secretion of GH.
What is the effect of a-adrenergic agents on GH? What is the effect of b-adrenergic agents on GH?
a- stimulate GH release
b- inhibit GH release
What are 7 physiological stimulators of GH secretion?
- protein rich meal [arg stim test]
- hypoglycemia [oppose insulin]
- stress
- exercise
- sleep
- a-adrenergic agents
- ghrelin
What are 2 physiological inhibitors of GH secretion?
- glucose load, fatty acids
2. b-adrenergic agents
What are the 4 ways GH deficiency can be acquired?
What are the genetic defects that can lead to GH deficiency?
Acquired:
- traumatic brain injury
- infection [GBS meningitis in infants]
- mass effect from intracranial tumors
- iatrogenic [surgical removal of craniopharygioma]
Genetic:
Mutation in TFs needed for pituitary development [HESX1, PIT1, PROP1] that lead to:
1. isolated GH deficiency
2. pan hypoparapituitarism
What are the manifestations of GH deficiency in children?
- Impaired growth [2 SD below age/sex adjusted height chart, delayed bone age, chubby]
- hypoglycemia - loss of counter regulation to insulin
A male baby has severe hypoglycemia and. microphallus. The size of the baby is normal. What is the likely problem?
Why is the size normal?
Congenital Pan-hypopituitarism:
1. hypoglycemia - lack of GH
2. microphallus - lack of gonadotropins
3 normal size - IGFII is responsible for in utero growth
What are the 2 signs of adult GH deficiency?
- increased adiposity
2. decreased bone mass
Random measurements of GH are useless due to ______________.
Circulating levels of _______ provide useful info about integrated GH levels, but the decision to institute GH therapy usually requires _______________.
Random GH is useless because pituitary releases it in a pulsatile manner.
IGF1 can give info about GH levels, but provocative testing is required when deciding to institute GH therapy.
What 3 stimulants are used for provocative testing of GH?
- Arginine - provides a protein load [stimulant of GH secretion]
- clonidine - a agonist [stimulant of GH secretion]
- insulin - induces hypoglycemia–>GH secretion
What is the usual cause of GH excess?
What is treatment?
GH excess is usually due to somatotrope adenomas of the pituitary that oversecrete GH but maintain some normal regulation.
- Treat with octreotide [SST analog]
Less commonly, adenomas secrete GH and prolactin. They are more difficult to treat but sometimes respond to dopamine agonists.
What is the manifestation of GH excess in children?
- Gigantism - because of increased growth rate and open long bone epiphyses
- glucose intolerance [prediabetic hyperglycemia]
What is the manifestation of GH excess in adults?
- Acromegaly- because the epiphyses are already closed and height cannot increase
- arthralgia
- glucose intolerance, hypertension
How is GH excess diagnosed?
- Elevated IGF1 is SUGGESTIVE
- oral glucose tolerance test- tests to see the glucose doesn’t suppress GH [like it should]
- MRI - assess for pituitary adenoma presence
What is treatment for GH excess?
- Transphenoidal surgery to remove the adenoma [success rate is low for macroadenomas]
- pituitary irradiation
- medical therapy
What drug is recombinant hGH?
somatropin - matches the exact sequence of human GH
What drug is indicated for:
- children with GH deficiency
- Turner’s, Noonan’s
- chronic renal disease
- idiopathic short stature
- prader-willi
- SGA
Somatropin - hGH
When is somatropin contraindicated?
- malignancy [active]
2. critically ill in the ICU
What is the mode by which somatropin is given?
When should the drug be given?
How receives higher dose, adults or children?
It is given SQ by injection, daily at bedtime to mimic the normal spike of secretion in sleep.
Dose is titrated so IGF1 is 2SD above mean for age.
Higher doses in children
What are the adverse affects associated with somatropin in children?
- headache
- increased intracranial hypertension
- slipped capital epiphyses [pain in knee, hip]
- does not CAUSE scoliosis, but worsens curvature during growth
What are the adverse effects of somatropin on adults?
How do you minimize them?
- edema
- arthralgia
- carpal tunnel syndrome
Minimize by starting at a lower dose and adjusting based on serum IGF1
What drug is recombinant human IGF-1?
How is it administered?
Mecasermin- administered 2x SQ injection daily
What drug is approved for:
- IGF1 deficiency
- Laron’s dwarfism
- STAT5b mutation - GH deficiency with Ab against GH
mecasermin - recombinant human IGF1
When is mecasermin contraindicated?
- active neoplasm
2. conditions that predispose to hypoglycemia [adrenal insufficiency]
What are adverse effects of mecasermin?
It is an IGF1 recombinant so too much can lead to:
- hypoglycemia [proinsulin and can act on IR]
- lipohypertrophy
Rarele, SCFE, and increased intracranial hypertension like GH excess
What are the 3 major medical options for the management of acromegaly?
- Octreotide - SST analog
- PEGvisomant - GHr antagonist
- Bromocriptine, Cabergoline [dop ag]
Describe the structure of octreotide.
How does this explain why it has a longer T1/2 than somatostatin?
How is the drug given?
8 AA length cyclic peptide.
It is resistant to proteolysis so it has a longer half life than SST
It is a peptide so cannot be given orally
What are the indications for using octreotide?
- acromegaly not responsive to surgery
- decreases portal hypertension so can be used for upper GI bleeds
- hyperinsulinism because SSTr on B-cells inhibit insulin release
What are the adverse effects of octreotide?
- gall stone formation or gall bladder sludge
2. nausea, vomiting
What are the 3 ways you should assess the response to ocreotide therapy?
- reduced symptoms of acromegaly [arthralgia, hyperglycemia, headaches, sweating]
- IGF1 levels should normalize
- GH following a glucose surge should improve
What drug is a GHR antagonist?
Describe the structure and dosage.
Pegvisomant is a pegylated recombinant GH that has mutations allowing it to bind but not activate GHR.
Dosage: SQ injection
What are the indications for pegvisomant?
Acromegaly that has not responded to surgery or SST analogs (octreotide)
What are the adverse effects of pegvisomant?
- hepatitis- so measure AST/ALT
2. tumor growth- lack of feedback
How do you evaluate the response of your patient to pegvisomant?
- cross reacts with GH in most assays
2. IGF1 should be used to adjust dose
Even though dopamine normally _________ GH secretion, DR agonists can be used to _________ GH especially from mixed adenomas.
Normally dopamine stimulates GH release.
It mixed adenomas {co-secretors} PRL and GH are being secreted, so dopamine agonists can actually reduce both.
What is the mechanism of PRL action? What other hormone does it have similar action to?
PRL and GH are from the same polypeptide hormone family so have similar signaling.
PRL binds to a single transmembrane receptor, attracts JAK2 which phosphorylates STAT5 which regulates expression of the target genes.
Describe the regulation of PRL.
What is inhibitory? What is stimulatory?
INHIBITORY: controlled by dopamine from the hypothalamic neurons. When it acts on D2 receptors on the lactrotrope cells in the pituitary, it inhibits the release of PRL.
STIMULATORY:
- estrogen stimulates synthesis and secretions [elevated PRL in pregnancy]
- suckling and breast manipulation are stimuli maintaining PRL post partum
- TRH at high levels stimulates [affects people with primary hypothyroidism]
What is the major action of PRL?
To stimulate post-partum milk production.
Elevated levels of PRL can inhibit male and female reproduction
What are the clinical features of hyperprolactinemia in women? Men?
Women: amenorrhea, galactorrhea in fertile females
Men: loss of libido, erectile dysfunction
What are 4 common etiologies for hyperprolactinemia?
- PRL pituitiary adenoma
- anti-psych drugs [dopamine antagonists]
- primary hypothyroidism [hormone spillover- TRH stimulates release of PRL
- PCOS- polycystic ovarian syndrome
What drugs can be used to treat hyperprolactinemia?
- bromocriptine
- cabergoline
Both are dopamine agonists
What are the adverse effects of bromocriptine?
- GI - nausea, vomit, diarrhea
- orthostasis and syncope [first dose]
- decreased efficacy of anti-psychotics
What are the 3 indications to use bromocriptine?
- hyperprolactinemia
- acromegaly
- Parkinson’s disease
What are the differences between bromocriptine and cabergoline?
Cabergoline has a higher affinity for the D2 receptor and has a longer half life so it can be given 2x weekly instead of daily like bromocriptine.
C is more $$$$ than B
Describe the structure of gonadotropins. What are the 4 and where are they made?
FSH, LH and TSH are made in the anterior pituitiary.
hCG is made in the placenta.
All 4 of these hormones share an alpha subunit and have a unique B subunit that confers specificity.
LH and hCG have similar B units also.
What is the mechanism of action of gonadotropins?
- Bind GCPR (FSH and LH receptors) in gonads [and in females corpus luteum]
- Gs activates adenylyl cyclase and increases cAMP
- steroid and gamete production is regulated
LH and hCG act through LH receptors
What is the target tissue/cell of FSH in males? What is the function?
FSH binds to Sertoli cells to:
- promote spermatogenesis
- stimulate inhibin secretion
What is the target tissue/cell of LH in males?
LH binds to Leydig cells to:
1. promote testosterone synthesis
What is the target tissue/cell of FSH in females?
What is the function?
FSH binds to granulosa cells to:
- support follicle growth
- stimulate inhibin secretion
- stimulate estrogen synthesis
What is the target tissue/cell of LH in females?
What is the function?
LH binds to theca cells, corpus luteum, follicles to:
- stimulate estrogen production
- stimulate progesterone production
What is the target tissue/cell of hCG?
What is the function?
hCG binds to corpus luteum to stimulate progesterone production
How does the hypothalamus help regulate gonadotropin secretion?
GnRH is released through the arcuate and mediobasal hypothalamus.
GnRH has a 2-4 minute half life so it is EXTREMELY pulsatile, releasing every hour. This pulsatility is crucial for gonadotropin secretion.
How does the anterior pituitiary regulate gonadotropin secretion?
Gonadotropes in the anterior pituitiary are activated by GnRH from the hypothalamus binding to their GCPR to stimulate synthesis and secretion of FSH and LH.
What happens if GnRH delivery is constant?
GnRH receptors are down regulated on gonadotropes in the ant. pituitiary and gonadotropin secretion is markedly decreased.
How do gonadotropins regulate the HPG Axis?
- Gonadal steroids [testosterone, estrogen, progesterone] feedback to inhibit GnRH secretion
* estrogen can have a rare positive feedback at a specific menstrual cycle stage - inhibin acts on gonadotropes to inhibit FSH secretion
- NE, opioids, dopamine, GABA regulate gonadotropin secretion
What are the 5 phases of reproductive function in women?
- follicular phase
- ovulation
- luteal phase
- menstruation
- fertilization
What occurs in the follicular phase of the women’s reproductive cycle?
Describe the pulse amplitude and frequency of gonadotropin release.
- Gonadotropins stimulate follicular growth
- follicular growth produces more estrogen
- estrogen stimulates growth of endometrium
- estrogen feeds back to hypothalamus and ant. pituitary to inhibit gonadotropin secretion
Gonadotropin pulses are small amplitude and occur frequently.
Describe what occurs during ovulation.
- estrogen levels rise (18-20) and now exert POSITIVE feedback on gonadotropes to stimulate gonadotropin secretion
- Increasing estrogen levels (150-200) in midcycle result in an LH surge
- LH binds to receptor in the ovary to produce ovulation
- residual follicle forms corpus luteum which produces estrogen and progesterone
What occurs in the luteal phase of female reproduction?
- Progesterone stimulates endometrium to vascularize and secrete mucus for implantation
- Progesterone feedback on the pituitary increases the amplitude of gonadotophin pulses but with longer intervals between pulses
What occurs during menstruation phase of the female reproductive cycle?
- egg is not fertilized
- corpus luteum regresses
- endometrium is not given hormonal support
- menses occurs
What occurs if fertilization of the egg takes place?
- Egg implants
2. trophoblasts synthesize hCG which supports estrogen and progesterone until wk 9
How is hCG used as a diagnostic tool?
- It can be measured in serum or urine to diagnose pregnancy
- germ cell tumors produce it so can measure as a tumor marker
How is LH used as a diagnostic tool?
- measured in urine to detect LH surge
2. help time intercourse for optimal fertilization probability
How can FSH and LH be used as a diagnostic tool?
They can be used to evaluate a child for precocious puberty or delayed puberty
What treatments are used as fertility treatments in women?
Exogenous gonadotropins can improve fertility by facilitating the maturation of oocytes.
- daily FSH injections
- hCG to induce ovulation
How are gonadotropins used exogenously for men?
- cryptochidism - testosterone can direct later stages of testicular descent and hCG can be used to induce descent of no anatomical barriers are present
- Fertilization - need both FSH and LH because LH will stimulate intracellular testosterone concentration to mature normal sperm and FSH stimulates Sertoli cells to promote spermatogenesis.
What are the 2 major adverse effects of fertility treatment?
- multiple gestations - exogenous gonadotropins can mature and ovulate multiple follicles
- Ovarian hyperstimulation syndrome - if FSH is too successful there will be increased vascular permeability, hypotension, ascites, pleural effusion and coagulation abnormalities
What are the complications associated with ovarian hyperstimulation syndrome?
What are the risks?
Complications:
- increased vascular permeability
- hypotension
- ascites
- pleural effusion
- coagulation problems
Risks:
- very high estrogen in late stages of FSH stimulation
- 3 or more large follicles on US examination
What are the 2 indications for using synthetic GnRH?
- distinguish btwn GnRH dependent and GnRH independent precocious puberty
- hypogonadotropic hypogonadism in the setting of normal gonadotropes
What drug is a GnRH agonist?
What are the 4 indications for its use?
Leuprolide
- GnRH-dependent precocious puberty
- hormone-dependent cancers
- endometriosis and uterine fibroids
- fertility treatment
What drug is a GnRH antagonist?
How does its action differ from GnRH agonist?
What are the 2 indications for its use?
Ganirelix is the antagonist and it will shut off gonadotropin release almost immediately without the transient flare seen with GnRH agonists
- fertilization treatment - allow proper timing of follicular maturation and shorten duration of IVF
- hormone responsive cancer
