Hypothalamic and Pituitary Hormones Flashcards
Receptor used for GH and prolactin?
JAK/STAT
Receptor used for TSH, FSH, LH, ACTH?
GPCR
Link hypothalamus to target hormone/mediator? (GHRH, somatostatin, TRH, CRH, GnRH, Dopamine)
GHRH (+), Somatostatin (-)
- stimulates GH and somatotropin release
- targets liver, muscle, bone, kidney, etc
- primary mediator is IGF-1 (insulin lifke growth factor-1, diabetogenic hormone)
TSH (+)
- stimulates TSH release
- targets adrenal cortex
- stimulates thyroxine and triidothyronine release
CRH (+)
- stimulates ACTH release from ant pituitary
- acts on adrenal cortex
- stimulates glucocorticoid, mineralocorticoid and androgen release
GnRH (+)
- stimulates FSH and LH release from ant pituitary
- targets gonads
- mediators are estrogen, progesterone and testosterone
Dopamine (-)
- inhibits prolactin release from ant pituitary
- acts on breasts
Growth hormone (aka Somatotropin)?
Required during childhood and adolescence. Binds JAK/STAT receptors causing dimerization and STAT phosphorylation that translocates to nucleus causing gene translocation.
Effects mediated by IGF-1
- stimulates long growth of bones (children) and increased bone density (adults)
- increased muscle mass
- increased GFR
- differentiation of pre-adipocytes to adipocytes
- anti-insulin action (diabetogenic hormone, decreasing glucose utilization and increased lipolysis)
- development and increased function of immune system
GH deficiency - genetic or damage to pituitary or hypothalamus leading to short and fat children or hypoglycemia (due to unopposed insulin action)
Criteria for dx of growth hormone deficiency…
- growth rate less than 4cm a year
- absence of serum GH response to two GH secretagogues
Recombinant Growth hormone?
Somatropin - recombinant GH
Somatrem - GH analog [everything is generally improved with an analog form]
Remains at active blood levels for 36 hours and is given 3-7 times a week subcutaneously.
Primary objective is for Growth, esp in pediatric pts with: GH deficiency, chronic renal failure, noonan syndrome, prader-willi syndrome, short stature homeobox, turners syndrome, small for gestational age, idiopathic short stature pts.
If they aren’t producing GH, which is why they are small, then this will help them. But if they are small for some other reason, it will help them a little, but it won’t make their height completely normal.
Can also be used to to improve metabolic state, increase body mass in HIV positive pts, improve GI function in pts with short bowel syndrome.
AE with CHILDREN - well tolerated, can cause scoliosis due to rapid growth, HYPOTHYROIDISM, intracranial HTN, otitis media (esp in Turner syndrome pts), pancreatitis, gynecomastia and nevus growth, diabetic syndrome with chronic use
AE with ADULTS - peripheral edema, myalgias, arthralgias, carpal tunnel syndrome, proliferative retinopathy
**contraindicated in pts with cytochrome P450 inducer or known malignancy b/c the GH will increase the rate of the growth
Mecasermin?
IGF-1 Analog use in IGF-1 deficiency which is due to a mutation in gene that encodes for GH receptor and development of neutralizing antibodies to GH.
This drug is a complex with recombinant human IGF-1 and recombinant human IGF-binding protein-3.
AE - hypoglycemia (so eat before or after admin), intracranial HTN, asymptomatic elevation of liver enzymes
Tx of growth hormone secreting tumors?
- GH receptor antagonists
- somatostatin analogs
- dopamine receptor agonists
- surgery - If possible!
Pegvisomant?
Growth hormone receptor antagonist thereby preventing dimerization of growth hormone receptors (JAK/STAT) preventing phosphorylation.
Octreotide?
Somatostatin analog - inhibits release of GH, TSH, glucagon, Insulin and gastrin
45x more potent in inhibiting GH release compared to somatostatin
2x more potent in reducing insulin secretion
t1/2 = 80 minutes
Octreotide acetate - long acting suspension given at 4 week intervals
Clinical application - reduce hormone-secretion tumor symptoms, localize neuroendocrine tumors, acute control of bleeding from esophageal varices
AE - nausea, vomiting, abdominal cramps, flatulence, steatorrhea, constipation, biliary sludge, gallstones, sinus bradycardia, vit B12 def (with long term use), pain at injection site (common)
Dopamine Agonists?
Bromocriptine and Cabergoline
Adenomas that secrete prolactin usually retain inhibition to dopamine therefore giving dopamine agonist inhibits prolactin adenomas.
Half life of Cabergoline is much longer compared to bromocriptine and can be given orally or via vaginal inserts.
Clinical application…
- hyperprolactinemia - dopamine shrinks pituitary prolactin-secreting tumor
- acromegaly
AE… nausea, headache, light headedness, orthostatic hypotension, fatigue, psych manifestations, cold-induced peripheral digital vasospams at high doses, pulmonary infiltrate at chronic high doses
Menotropins?
hMG - purified extracts of FSH and LH
**menotropins or human menopausal gonadotropins
Used to treat infertility.
Follitropin and Urofollitropin?
Purified FSH
- rFSH [follitropin a and B] = recombinant FSH
- uFSH = purified human FSH extract
Choriogonadotropin a (rhCG)?
recombinant form of hCG given SC or IM daily
*acts through GPCR to coordinate patterns of FSH and LH secretion during menstrual cycle
Clinical application
- ovulation induction
- male infertility
AE…
- ovarian hyperstimulation syndrome (women)
- multiple pregnancies (women)
- headache, depression, edema, precocious puberty (women)
- gynecomastia (men)
GnRH and analogs?
Gonadorelin = gonadotropin-releasing hormone (synthetic human GnRH)
Goserelin, Leuprolide, Nafarelin = gonadotropin-releasing hormone analog – these are more potent and longer lasting compared to Gonadorelin
GnRH binds to GPCR on gonadotroph cell membranes. It’s administration can be pulsatile GnRH which stimulates release of LH and FSH. Pulsatile prevents the negative feedback which prevents LH and FSH release. GnRH can also be given in a sustained non-pulsatile manner where GnRH inhibits FSH and LH release leading to hypogonadism.
Continuous admin gives a biphasic response – 1st week it acts as an agonist increasing LH and FSH then after 1 week leads to inhibitory action down regulating LH and FSH.
Clinical application (stimulation)…
- female infertility (inconvenient and costly)
- male infertility (pulsatile gonadorelin in men with hypothalamic hypogonadotropic hypogonadism)
- dx of LH responsiveness - whether delayed puberty is due to constitutional delay of hypogonadotropic hypogonadism
Clinical application (suppression)…
- controlled ovarian hyperstimulation (Leuprolide, nafarelin) – suppresses endogenous LH surge that could prematurely trigger ovulation
- endometriosis (leuprolide, goserelin, nafarelin) – by eliminating cyclical estrogen/progesterone concentrations pain from endometriosis can be relieved
- uterine leoimyomata (fibroids) (leuprolide, goserelin, nafarelin) - reduce size of fibroid with supplemental iron
- Prostate cancer (leuprolide, goserelin) - used with androgen receptor antagonists to act as effective castration in reducing serum testosterone
- central precocious puberty (leuprolide, nafarelin)
- advanced breast and ovarian cancer
- tx of amenorrhea and infertility in women with PCOD
- thinning of endometrial lining to prepare women for endometrial ablation to tx dysfunctional uterine bleeding
AE… headache, light-headedness, nausea, flushing, swelling at SC site, generalized HSN dermatitis, acute HSN reaction, sudden pituitary apoplexy and blindness
AE of continuous tx
FOR WOMEN - menopausal symtpoms, depression, diminished libido, generalized pain, ovarian cysts, reduced bone density and osteoporosis, DO NOT GIVE IN PREGNANT OR BREAST-FEEDING WOMEN
AE FOR MEN - menopausal symptoms, gynecomastia, reduced bone density
GnRH antagonists?
Cetrorelix and Ganirelix
Used for suppression of gonadotropin production - prevent LH surge during controlled ovarian hyperstimulation
