Hypothalamic and Pituitary Hormones Flashcards Preview

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Flashcards in Hypothalamic and Pituitary Hormones Deck (20):
1

Receptor used for GH and prolactin?

JAK/STAT

2

Receptor used for TSH, FSH, LH, ACTH?

GPCR

3

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

4

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...
1. growth rate less than 4cm a year
2. absence of serum GH response to two GH secretagogues

5

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

6

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

7

Tx of growth hormone secreting tumors?

1. GH receptor antagonists
2. somatostatin analogs
3. dopamine receptor agonists
4. surgery - If possible!

8

Pegvisomant?

Growth hormone receptor antagonist thereby preventing dimerization of growth hormone receptors (JAK/STAT) preventing phosphorylation.

9

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)

10

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...
1. hyperprolactinemia - dopamine shrinks pituitary prolactin-secreting tumor
2. 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

11

Menotropins?

hMG - purified extracts of FSH and LH
**menotropins or human menopausal gonadotropins

Used to treat infertility.

12

Follitropin and Urofollitropin?

Purified FSH
*rFSH [follitropin a and B] = recombinant FSH
*uFSH = purified human FSH extract

13

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
1. ovulation induction
2. male infertility

AE...
1. ovarian hyperstimulation syndrome (women)
2. multiple pregnancies (women)
3. headache, depression, edema, precocious puberty (women)
4. gynecomastia (men)

14

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)...
1. female infertility (inconvenient and costly)
2. male infertility (pulsatile gonadorelin in men with hypothalamic hypogonadotropic hypogonadism)
3. dx of LH responsiveness - whether delayed puberty is due to constitutional delay of hypogonadotropic hypogonadism

Clinical application (suppression)...
1. controlled ovarian hyperstimulation (Leuprolide, nafarelin) -- suppresses endogenous LH surge that could prematurely trigger ovulation
2. endometriosis (leuprolide, goserelin, nafarelin) -- by eliminating cyclical estrogen/progesterone concentrations pain from endometriosis can be relieved
3. uterine leoimyomata (fibroids) (leuprolide, goserelin, nafarelin) - reduce size of fibroid with supplemental iron
4. Prostate cancer (leuprolide, goserelin) - used with androgen receptor antagonists to act as effective castration in reducing serum testosterone
5. central precocious puberty (leuprolide, nafarelin)
6. advanced breast and ovarian cancer
7. tx of amenorrhea and infertility in women with PCOD
8. 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


15

GnRH antagonists?

Cetrorelix and Ganirelix

Used for suppression of gonadotropin production - prevent LH surge during controlled ovarian hyperstimulation

16

ACTH analogs?

Corticotropin and Cosyntropin

Limited utility as a therapeutic agent

• Act via MC2R (GPCR to cAMP) to stimulate adrenal cortex to secrete glucocorticoids, mineralocorticoids and
androgen precursor androgen precursor

• ACTH normally released from pituitary in pulses with
highest concentration at ~ 6am and lowest in evening. Secretion also stimulated by stress

• Cortisol suppresses ACTH release via negative feedback.

Used as dx tool in Addison's disease or inadequate ACTH secretion as well as WEST syndrome (infantile spasm) treatment

AE - similar to glucocorticoids

17

Oxytocin?

-Oxytocin acts on GPCR to stimulate release of prostaglandings and leukotrienes that augment uterine contractions

-Small doses to evoke pulsatile contractions
-higher doses you evoke sustained contractions (as well as has weak antidiuretic/pressor activity)

Give via IV if used for initiation and augmentation of labor.
Give via IM to control postpartum bleeding.

Uses...
1. labor induction
2. augment normal labor
3. control uterine hemorrhage

AE - excessive stimulation of uterine contraction, inadvertent activation of vasopressin receptor, bolus injection may lead to hypotension

Contraindicated - fetal distress, prematurity, abnormal fetal presentation, cephalopelvic disproportion, uterine rupture predisposition

18

Atosiban?

Oxytocin Antagonist - used for treatment of preterm labor, not in the US!

19

ADH agonists?

Vaspressin and Desmopressin

-Vasopressin is usually released in response to falling plasma tonicity or falling BP as it has both ANTIDIURETIC and VASOPRESOR activities

-Desmopressin is a long-acting synthetic analog of vasopressin that has minimal V1 activity -- has almost 4000 times more antidiuretic activity compared to vasopressor activity

-V1R - vasoconstriction of vascular SM
-V2R - renal tubular cells to increase water permeability and water reabsorption

Clinical application...
1. DOC for diabetes insupidus
2. Esophageal bleeding and colonic diverticular bleeding (vasopressin)
3. Coagulopathy tx in hemophilia A and vWF disease (Desmopressin)

AE - headache, nausea, abdominal cramps, allergic reaction

Overdose = hyponatremia and seizures

20

ADH antagonists?

Conivaptan - affinity to both V1 and V2 receptors leading to their inhibition

*approved for use in patients with hyponatremia due to elevated vasopressin