Endo (pt 2/7) GH and FSH/LH Flashcards
Explain how the hypothalamus plays a role in the release of hormones from the anterior pituitary?
1) Releasing hormones are synthesized by hypothalamic neurons and travel down axons to diffuse into primary plexus of the hypophyseal portal system
2) Releasing hormone is then carried by hypophyseal portal veins to the secondary plexus, and distributed to target cells within ant. Pituitary
3) A specific Hormone is then released from the target cell in the Ant. Pituitary
What is the Hypothalamic Hormone associated with TSH?
Thyrotropin Releasing Hormone (TRH) +
-Regulated by feedback inhibition by the levels of the hormones whose production they control
What is the Hypothalamic Hormone associated with ACTH?
Corticotropin Releasing Hormone (CRH) +
-Regulated by feedback inhibition by the levels of the hormones whose production they control
What is the Hypothalamic Hormone associated with FSH and LH?
Gonadotropin Releasing Hormone (GnRH) +
-Regulated by feedback inhibition by the levels of the hormones whose production they control
What Hypothalamic Hormones are associated with Growth Hormone regulation?
Growth Hormone Releasing Hormone (GHRH) stimulates GH production
Somatostatin inhibits GH production
What Hypothalamic Hormone stimulates Prolactin secretion?
None; trick question. The Hypothalamus does not produce a hormone that specifically stimulates Prolactin secretion.
What Hypothalamic Hormone inhibits Prolactin secretion?
Dopamine -
____ can stimulate Prolactin release when ____ concentrations are high, such as in the setting of primary Hypothyroidism.
TRH; TRH
Which anterior pituitary hormone closely resembles Prolactin?
Growth Hormone (Somatotropin)
-Required during childhood and adolescence for the attainment of normal adult size
-Important effects on Lipid, Protein, and Carb metabolism; lean body mass, & bone density
Growth Hormone
Recombinant form of GH.
-Administered SQ 6-7 x’s per week (absorption = 70-90%)
-1/2 life = 1.75 hours
-Duration = 36 hours
Somatropin (rhGH)
Growth promoting effects of GH are mediated principally through an increased production of?
Insulin-Like Growth Factor 1 (IGF-1)
Produced in the Liver.
-Essential for normal prenatal and postnatal growth
-Becomes dependent on GH during the 1st year of life
IGF-1
Stimulates:
-IGF-1 production in bone, cartilage, muscle, kidney & other tissues
-Longitudinal bone growth
-Anabolic effects in muscle
-Catabolic effects in lipid cells
Growth Hormone
T/F: You can safely ingest native GH?
False; ingestion of native GH causes prion disease.
-Rapidly progressive and fatal
-Creutzfeldt-Jakob Dz
-Variant Creutzfeldt-Jakob Dz (Human version of mad-cow dz)
What are 2 examples of Syndromes caused by GH deficiency?
1) Turner Syndrome
2) Prader Willi Syndrome
X-Linked recessive GH deficiency.
-Short stature, low hairline
-Shield-shaped thorax, widely spaced nipples
-Constriction of aorta
-No menstruation, rudimentary ovaries, Poor breast development
Turner Syndrome
Autosomal Dominant (M or F) obesity in childhood.
Prader Willi Syndrome
How do you treat genetic syndromes caused by GH deficiency?
Recombinant Somatotropin
What are acquired causes of GH deficiency?
Pituitary/Hypothalamus damage (intracranial tumors, infections, infiltrative or hemorrhagic processes, or irradiation)
Has 191 Amino Acid Sequence identical to native GH.
-Increases activity of the CYP450 (CYP450 Inducer)
Somatropin
Somatropin may ____ the serum levels of drugs metabolized by CYP450.
Reduce
What are clinical uses for Somatropin?
-Growth Failure in pediatric patients associated with GH deficiency, chronic renal insufficiency post-transplant, Noonan Syndrome, Prader-Willi, Turner syndrome, idiopathic short stature
-GH deficiency in adults
-Wasting in patients with HIV
-Short bowel syndrome in patients receiving specialized nutritional support
-Used by athletes to increase muscle mass and improve performance (banned)
-Used in 1993 in rbGH (recombinant bovine) to increase milk production in dairy cattle. Mastitis = inc abx residue in milk.
What are adverse effects associated with Somatropin?
Adverse effects are relatively rare - occur more often in adults than in children:
Pseudotumor cerebri
Slipped capital femoral epiphysis
Progression of scoliosis
Edema
Hyperglycemia
Increased risk of asphyxiation in severely obese patients with Prader-Willi syndrome & upper airway obstruction or OSA
Pancreatitis
Gynecomastia
Nevus growth
↑CYP 450 Enzymes (Inducers)
What are the contraindications for Somatropin?
-Patients with known malignancy
-Critically ill (known to increase mortality)
Long term effects of GH treatment in childhood is ______.
Unknown
Recombinant human IGF-1 (rhIGF-1)
-Used in the tx of severe IGF-1 deficiency that is NOT responsive to GH
-Adverse Effects: hypoglycemia, intracranial HTN, Adenotonsillar hypertrophy, elevated LFTs
-Give carb snack before/after administration
Mecasermin or Mecasermin Rinfabate (GH Agonists)
rhIGF-1 added to recombinant human insulin-like growth factor binding protein -3 (rhIGFBP-3).
-rhIGFBP-3 is produced in the liver, under the control of GH
-Adding the binding protein significantly increases the 1/2 life
Mecasermin Rinfabate
Increased release of GH after puberty ends (closure of the epiphyses)
-Adults 30-50 years old
-Abnormal growth of cartilage and bone tissue, as well as other organs (skin, muscle, heart, liver, & GI tract)
Acromegaly
What are S/sx of Acromegaly?
-Acral overgrowth (pertaining to peripheral parts): enlarged facial bones, enlarged hands/feet, thickening of skin, etc.
-Muscle weakness & neuropathies
-Cardiac enlargement (HTN/CHF - most die of CV disease)
-Large lung volumes (inc dead space)
-Large upper airway
What are the airway concerns with a patient with Acromegaly?
Overgrowth of tissues in upper airway and larynx:
-Sleep Apnea is common
-Large upper airway = inc dead space = v/q mismatch
-Goiter common
-Difficult mask fit (longer distance between teeth and larynx)
-Difficult intubation (large tongue)
What causes 95% of Acromegaly cases?
Pituitary Adenomas. Slow progressing, so usually macroadenomas.
-Rarely caused by excessive GH from somatotrophic hyperplasia.
What is the treatment for Acromegaly?
1st line: Surgery!!!!
2nd: Drugs:
-Somatostatin analogues (Octreotide)
-Dopamine agonists (Bromocriptine)
-GH receptor antagonist (Pegvisomant- give SQ everyday)
With Tx, LV hypertrophy can be resolved, but skeletal/soft tissue changes are permanent.
What is the surgery for tx of Acromegaly?
Endoscopic transsphenoidal surgery (1st line therapy before meds)
What are the drugs given for Acromegaly if surgery is unsuccessful?
-Somatostatin analogs (Octreotide or Lanreotide)
-Dopamine Receptor Agonists
-GH receptor antagonists (Pegvisomant)
Where is Somatostatin found?
-Hypothalamus and other areas of the CNS
-Pancreas & other areas of the GI tract
What does Somatostatin inhibit the release of?
-GH
-TSH
-Glucagon
-Insulin
-Gastrin
Why does endogenous somatostatin have limited clinical usefulness?
Short duration of action. T1/2 of 1-3 min (Analogs were developed to increase biologic activity - octreotide)
A GH receptor antagonist for the treatment of Acromegaly.
-Prevents GH from activating the GH signaling pathways
-Competitive antagonist - binds to receptor so GH can’t bind
-May increase GH levels and inc adenoma growth
-Increases in liver enzymes without Liver failure have been reported
Pegvisomant
What is the treatment for Acromegaly for patients unresponsive to surgery and meds?
Radiation therapy
What is the most widely used somatostatin analog?
Octreotide
Octreotide is ____x’s more potent than Somatostatin at decreasing GH release.
45 times
Octreotide is ___x’s more potent than Somatostatin at decreasing insulin secretion from pancreatic beta cells
2 times
Octreotide’s half life is ____ x’s longer than Somatostatins.
30 times longer (T1/2 = 80 minutes)
What is Octreotide effective at treating?
Acromegaly
Carcinoid syndrome
Gastrinoma
Glucagonoma
Insulinoma
VIPoma
ACTH-secreting tumor
Portal hypertension
Diarrhea from HIV, diabetic neuropathy, chemotherapy, radiation
Acute control of bleeding from esophageal varicies
What are the adverse effects associated with Octreotide?
-GI Symptoms (abd pain, n/v, bulking bowel mvmts)
-Biliary sludge (Gallstones 20-30%)
-CV: Sinus Brady in 25%, conduction disturbances in 10%
-B12 deficiency
An Octapeptide, long-acting formulation similar to Octreotide.
-Tx of Acromegaly
-Decreases GH levels and normalizes IGF-1 concentrations
-not used as often
Lanreotide
-Stimulate spermatogenesis in men
-Induce ovarian follicle development in women
-Most common clinical use if for controlled ovarian stimulation for in vitro fertilization
LH/FSH
A placental glycoprotein nearly identical to LH
Actions are mediated through LH receptors.
hCG
-Purified extract of FSH & LH from the urine of menopausal women.
-30 L of urine needed to extract a full cycle.
-Natural FSH & LH
-Usually given IM (can be SQ)
Menotropins (Human Menopausal Gonadotropin or hMG)
Purified FSH from the urine of menopausal women.
-Usually given IM (could be SQ)
-3 versions
1) Urofollitropin (removed from market - natural)
2) Follitropin alpha
3) Follitropin beta
What preparations of purified FSH are very expensive and synthetic?
Follitropin alpha and beta
Recombinant LH (synthetic)
-T1/2 of 10 hours
-Used in combo with Follitropin alpha for infertile women w/ profound LH deficiency
-Usually given IM (could be SQ)
Lutropin Alpha
Can be natural form: purified extract from human placenta (given IM) or synthetic form: recombinant form (given weight-based dosing SQ)
hCG
What is the name for the recombinant form of hCG?
Choriogonadotropin Alpha (remember: weight based dosing with SQ admin)
FSH, LH, hCG, ACTH, and TSH all work their effects through what kind of receptors?
GPCRs
What are gonadotropins (FSH, LH, hCG) used for?
-Ovulation induction for women with anovulation
-Controlled ovarian hyperstimulation (IVF) - risk for multiple pregnancies and ovarian hyperstimulation syndrome
-Male infertility
What are the outdated uses for Gonadotropins (FSH, LH, and hCG)?
No longer used for:
-Tx of prepubertal crypto (absence of one or both testes from descending). Surgery is a better approach.
-HCG for weight loss (with severe calorie restriction - <1200 calories/day)
