What are the three structural classes of anterior pituitary hormones?
Single-chain protein hormones / Dimeric proteins that activate GPCRs / Single peptides cleaved from larger precursors
What are the two examples of single-chain protein hormones from the anterior pituitary?
Growth Hormone and Prolactin
What are the three dimeric proteins from the anterior pituitary that activate GPCRs?
Thyroid Stimulating Hormone, Follicle Stimulating Hormone, Luteinizing Hormone
Which anterior pituitary hormone is a single peptide cleaved from a larger precursor?
Which hormones share identical alpha-subunits?
TSH, FSH and LH
What is the most abundant anterior pituitary hormone?
Growth Hormone (GH)
Which anterior pituitary hormone is unique in that a specific releasing hormone that stimulates its release has not yet been identified?
Aside from somatostatin analogs and GH receptor antagonists, what other class can be used to treat acromegaly?
Dopamine Receptor Agonists
What gonadal steroid hormone increases expression of oxytocin receptors?
What pituitary hormones contain the fewest number of amino acids?
Oxytocin, Vasopressin and Desmopressin
Of the two pituitary lobes, which is supported by a portal system?
Anterior Pituitary Lobe
What are some examples of releasing hormones that go to the anterior pituitary lobe?
Growth Hormone-Releasing Hormone (GHRH), Thyrotopin-Releasing Hormone (TRH), Corticotropin-Releasing Hormone (CRH), Gonadotopin-Releasing Hormone (GnRH)
What are the anterior pituitary hormones?
Growth Hormone (somatotropin), Thyroid-Stimulating Hormone (thyrotropin), Prolactin, Adrenocorticotropic Hormone, and Gondatotropins
What are the two gonadotropins?
Luteinizing Hormone and Follicle-Stimulating Hormones
What are the two posterior pituitary hormones?
Oxytocin and Antidiuretic Hormone (aka vasopressin)
What is the difference between the anterior and posterior pituitary hormones?
Posterior do not require the presence of releasing hormones from a portal system - they get released from modified nerve endings arising from structures in the brain
In addition to negative feedback loops, what are two endogenous inhibitors of hormone -releasing hormones?
Dopamine and Somatostatin
What are Hormone 1 and Hormone 2 resulting from TRH?
Hormone 1 = TSH
Hormone 2 = Thyroid Hormone
What are Hormone 1 and Hormone 2 resulting from CRH?
Hormone 1 = ACTH
Hormone 2 = Glucocorticosteroids
What are Hormone 1 and Hormone 2 resulting from GnRH?
Hormone 1 = FSH and LH
Hormone 2 from FSH = Inhibin (testes) and Inhibin/Estrogens (ovaries)
Hormone 2 from LH = Progestins/Estrogens (ovaries) and Androgens (testes)
What type of receptor interacts with GHRH?
Gs, releasing GH
What are the four targets for GH?
Liver, Bone, Adipocytes and Muscle
What is the main product of GH stimulation at the four targets (also the primary peripheral effector of GH effects)?
Insulin Growth Factor 1 (IGF-1)
What type of receptor interacts with SST?
Gi, inhibiting release of GHRH/GH
What compound released by the stomach can inhibit SST at the hypothalamus?
Ghrelin (leading to an increase in GHRH)
What typically-inhibitory neurotransmitter is actually stimulatory in releasing IGF-1?
What is required for GH receptor activation?
dimerization between two receptors
Which two pathways are kicked off after GHR activation?
JAK/STAT and Ras/MAPK
What are some physiological effects of GH?
increasing lipolysis and gluconeogenesis
What are some physiological effects of IGF-1?
increasing bone growth and muscle mass
What is the term for GH excess before epiphyseal plate closure?
What is the term for GH excess after epiphyseal plate closure?
What are two agents to treat GH deficiency?
HGH (recombinant GH) and Mecasermin (recombinant IGF-1)
Which route is contraindicated in HGH?
Oral (b/c it is a peptide)
At what time should HGH be administered?
What is a rare but dangerous AE of HGH in children?
What is required in order for rIGF-1 to work?
has to be coupled with a binding protein to transport it (rIGFBP-3)
What is a major AE for rIGF-1?
Hypoglycemia (b/c insulin moves glucose into cells)
What should you counsel patients taking rIGF-1 with regards to food?
Eat something 15-30 minutes prior to administration
What are two methods for treating excess GH?
shut down production of GH / shut down effects of GH by antagonizing GHR
What somatostatin analog is used to treat excess GH?
Where does Octreotide have its activity?
at both the pituitary (preventing GH release) and hypothalamus (preventing GHRH release) levels
Which SST receptors will Octreotide preferrentially bind to?
SST-2 and SST-5
How often should Octreotide IM be administered?
Q4W (b/c it is a depot formulation)
What effect does Octreotide have?
Decreases GH release, normalizes IGF-1 levels and also decreases TSH release
What other issues will Octreotide be used for?
various GI issues
What is a common ADR for Octreotide?
What is another SST analog with similar profile to Octreotide?
What is the name of the PEG derivative of a mutant GH?
Where does Pegvisomant have its action?
at the GH receptor (binds/dimerizes, but doesn't activate)
What are the effects of Pegvisomant?
decreased GH effects and decreased IGF-1 synthesis/secretion
What can you see increase with the use of Pegvisomant?
Increased GHRH and GH levels (B/c you have inhibited the negative feedback loop) - levels don't increase enough to overcome competitive inhibition of GHR
What is an AE you have to watch out for with Pegvisomant?
Allergic reaction to the drug (due to formation of Ab against it)
How do the levels of prolactin compare in males and females?
Males - very low / Females - particularly high in pregnancy and nursing
With regards to the mother's milk, what is the difference between prolactin and oxytocin?
Prolactin stimulates production of the milk / Oxytocin stimulates the letdown of the milk
What can inhibit release of Prolactin?
Dopamine (particularly D2), which before being completely identified, was simply known as Prolactin Inhibitory Factor
What can happen if you give a DA receptor antagonist with regards to prolactin?
You will see increase in prolactin levels, leading to breast enlargement in males
What are the physiological effects of prolactin?
mammary gland development and milk production
What other ligand besides prolactin hit prolactin receptors?
GH (can actually mimic prolactin at high enough concentrations)
What class of agents will you use to treat hyperprolactinemia?
DA receptor agonists (Bromocriptine and Carbergoline)
Which DA receptor agonist is used in hyperprolactinemia but not indicated for Parkinsons?
What is the benefit of using Cabergoline over Bromocriptine in hyperprolactinemia?
Longer half-life (65 h vs 2-8 h) and less nausea
What controls the normal release of GnRH in the hypothalamus?
a neural pulse generator
When is the neural pulse generator extremely active in releasing GnRH?
Early in life and again during puberty
What occurs when you give continuous administration of GnRH?
downregulation of receptors (which is why you have intermittent release in normal physiology)
What is therapeutic use of continuous administration of GnRH?
downregulate receptors in prostate cancer to get an almost-total shut off of testosterone
Of the sex hormones, which is only negative feedback?
Inhibin (negative feedback on FSH)
Of the sex hormones, which are both positive and negative feedback?
Estrogen, Progestin, and Testosterone
How are GnRH receptors classified?
Gq - lead to increased presence of Ca important to the secretion process
How are gonadotropin receptors classified?
Gs - leading to release of sex hormones
What other ligand besides LH hits LH receptors?
What are the effects of LH in males and females?
males - stimulates synthesis of testosterone / females - stimulates synthesis of androstenedione
What is androstenedione converted to and to what effect in women?
17-beta-estradiol / required for rupture of the dominant follicle during ovulation AND required for synthesis of progesterone
What are the effects of FSH in males and females?
males - stimulates sperm maturation / females - stimulates growth of ovarian follicles, induces expression of LH receptors and regulates activity of aromatase
What are some synthetic GnRH analogs?
Leuprolide, Nafarelin, Histrelin, Triptorelin, Goserelin
What is the difference between recombinant GnRH and GnRH analogs?
recombinant has smaller half-life and requires more drug than analogs / analogs are longer acting and more potent
When you see the use of GnRH agonists, what should you think?
What are some diagnostic uses of GnRH agonists?
evaluation of hypogonadotropic hypogonadism / Differentiate central (GnRH-dependent) from peripheral (GnRH-independent) precocious puberty
If you administer a GnRH agonist and see a surge in LH, what will that indicate?
That there is a problem in the hypothalamus and not the pituitary (not making enough GnRH)
What are some therapeutic uses of GnRH agonists?
Female/male infertility, suppression of gonadotropin secretion (via downregulation/desensitization), gonadotropin-dependent precocious puberty, hormone response tumors, endometriosis and uterine leiomyoma
What are some AE of GnRH agonists?
HA, light-headedness, nausea and flushing (for recombinant)
hot flashes/sweats, HA, vaginal dryness/atrophy, decreased bone density (analogs)
What is the benefit of giving a GnRH antagonist over an GnRH agonist in shutting down receptors?
avoid the initial blip in hormone release, so you end up with more complete coverage
What are two GnRH antagonists used in controlled ovarian hyperstimulation procedures?
Ganirelix and cetrorelix
What GnRh antagonist is used in advanced prostate cancer?
What is a major AE of Abarelix?
significant hypersensitivity reactions (dermatological, hypotension and syncope)
What diagnostic tool is hCG used for?
What diagnostic tool is LH used for?
timing of ovulation (see a spike 36 h prior to ovulation)
What are some examples of therapeutic gonadotropins?
Urofollitropin (uFSH - taken from urine of pregnant women), Lutropin alpha (rLH), Choriogonadotropin alpha (rhCG), Menotropins
What are some therapeutic uses of gonadotropins?
female and male infertility and cryptorchidism
How will gonadotropin-use help in female infertility?
induction of ovulation (use in conjunction with LH)
How will gonadotropin-use help in male infertility?
increased testosterone synthesis (hCG) or induce sperm formation/development (Menotropins or rFSH)
What gonadotropin is used for cryptorchidism?
hCG (recall that it acts at LH receptors)
What are some AE of gonadotropins?
Ovarian hyperstimulation syndrome, multiple births, increased risk of ovarian cancer, gynecomastia (feminization in males)
What compound can inhibit vasopressin (ADH)?
At high doses, what mimics the effects of vasopressin?
What are some physiological effects of oxytocin?
activates GPCRs (Gq) which enhance VGCC activity and prostaglandin production = increase in Ca leading to uterine contraction
How should oxytocin be administered?
Continuous IV drip (due to short half-life of 3-5 min)
What are some therapeutic uses of oxytocin?
induction/augmentation of labor, control of postpartum labor and oxytocin challenge test (to evaluate fetal response to drug)
What are some AE of oxytocin?
uterine hyperstimulation may occur (too frequent contractions/tetany), antidiuretic effects (fluid retention/hypernatremia)