Other Endocrine Disorders & Prostate Cancer Flashcards
(35 cards)
Hypothalamus often secretes a __________ that
acts on the hypothalamus to modify hormone
secretion
releasing factor
ex:
– Thyrotropin release factor
– Gonadotropin releasing factor
Hormone release regulates its secretion via
negative feedback mechanisms on?
– Hypothalamus
– Anterior pituitary
Growth Hormone
describe its secretion
what hormone regulates its secretion
Growth hormone (GH) is the most abundant ant pituitary hormone (recombinant GH = somatropin)
– Secretion rates high in newborns and decrease at ~4 years of age and maintained till puberty, followed by further declines
– Secretion regulated by GHRF
- increases during deep sleep for children 10-100x
- doping not easily detected with high flucuations
Growth Hormone
Clinical use? (3)
AE? (2)
– To treat individuals with pituitary dwarfism (GH deficiency)
– To promote growth and correct short stature in women with Turner’s Syndrome (one X chromosome missing or altered)
– Used illicitly by athletes to increase muscle mass (e.g. Barry Bonds)
- similar to acromegaly: hypertension, carpal tunnel syndrome*, diabetes
- cardiomegaly*: enlarged heart
- cardiomyopathy: dysfunc in absence of atherosclerosis
Growth Hormone
what kind of receptor?
what does it stimulate?
GH receptor is a class I cytokine receptor
– GH and its analogues stimulate growth
– Stimulates hepatic production of insulin-like growth factor (IGF)
– IGF promotes uptake of amino acids and protein synthesis in skeletal muscle & cartilage of long bones
– Mecasermin can also be used (recombinant IGF-1)
Back then - get from cadavers - degenrative diseases
Now with recombinant technology, bacterial culture
Humans only respond to human GH
Growth Hormone
IGF Receptor Signaling
activates? (2)
IGF-1 binding to the IGF-1 receptors stimulates cell growth through 2 pathways involving initial activation/binding of insulin receptor substrate (IRS) proteins
– Activation of Ras: mitogen-activated protein kinase (MAPK) turns on DNA required for cell prolif
– Activation of Akt
▪ Leads to activation of mTOR (potent stimulator of protein synthesis)
- cell survival, cell growth, cell cycle
Growth Hormone Receptor Antagonists
what is acromegaly?
what is a GH receptor antagonist?
Acromegaly
– A disorder characterized via excess growth hormone secretion in adults (surgical removal is an option)
• Pegvisomant
– Modified analogue of GH that prevents actions of GH on liver receptors to stimulate IGF secretion
• Pharmacokinetics
– Subcutaneous injection (protein)
– Addition of polyethylene glycol increases half-life to ~2 days
Growth Hormone Receptor Antagonists
AE?
– Elevated liver enzymes (contraindicated in people with severe liver disease)
Other Treatments for Acromegaly
Somatostatin Analogues
Name 3
Somatostatin inhibits secretion of ant pit growth hormone (and many others)
– Octreotide - primary use for excess GH
– Lanreotide - used for thyroid
– Pasireotide - excess glucocorticoid secretion
Other Treatments for Acromegaly
Somatostatin Analogues
MOA?
– Mimic actions of somatostatin (octreotide signals through somatostatin receptor 2/5)
- act on ant pit to prevent GH release
– Inhibit GH secretion
Other Treatments for Acromegaly
Somatostatin Analogues
AE?
contraindication?
– Cardiovascular (*sinus bradycardia)
– GI (abdominal pain, diarrhea, nausea)
– CNS (headache, fatigue)
- pain at injection site
• Contraindicated/Use Caution
– Type 1 diabetes
▪ Hypoglycemia
Somatostatin can cause hypoglycemia or hyperglycemia
Decreases insulin from beta and glucagon from alpha cell
-Depends on balance of insulin and glucagon secretion
• Surgery/Radiation therapy arepreferred treatment options (most effective in small tumors)
Hormone Replacement Therapy
how does it work?
what are the benefits?
For post-menopause
– Cyclic or continuous administration of low dose estrogen with or without a progestogen (not treatmnet of choice)
Benefits:
– Prevent menopausal symptoms (e.g. hot flashes, chills, night
sweats, vaginal dryness, mood changes, etc.)
– Protect against osteoporosis
– Does not reduce the risk of coronary heart disease
- CV risk increases after post-menopause but not due to lack of estrogen
Hormone Replacement Therapy
AE? (2)
– Cyclical withdrawal bleeding
– *Increased risk of endometrial cancer (w/o progestogen)
– *Increase risk for breast cancer (related to duration of use)
– Increased risk of thromboembolism, greater than 5 year use
Testosterone
functions? pharmacology?
– Maturation of reproductive organs and development of secondary sexual characteristics
– Maintenance of spermatogenesis & maturation of spermatozoa
- LH = ICSH (interstitial cell stim hormone)
- Sertoli cells and interstitial to increase secretion of testosterone
– Testosterone acts via nuclear receptor signaling (androgen receptor (AR))
– Dihydrotestosterone - binds androgen receptor - dimerizes, nuclear receptor
Testosterone HRT
what can it treat?
– Male hypogonadism due to pituitary or testicular disease
– Female hyposexuality following ovariectomy
Free hormone is the active one that mediates effects
negative feedback mechanism
Testosterone HRT
AE? (3)
– *Infertility with continued use (decreased gonadotropin release) – *Salt & water retention (edema) – *Acne – Impaired growth (children) – Masculinization in women
Prostate cancer
what happens with estrogen and testosterone?
• Tumors in hormone sensitive tissues (e.g. prostate
gland, breast) may be hormone dependent
• Growth of these tumors can be inhibited by;
- Hormone agonists/antagonists
- Agents that inhibit hormone synthesis
Malignant cells express repceptors of estrogen or testosterone - excess stimulates growth of tumor
- manipulate hor,ones to treat prostate cancer
Prostate cancer
Gonadotropin Releasing Hormone Analogues (5)
– Gonadorelin (synthetic GnRH) – Buserelin – Leuprorelin – Goserelin – Nafarelin
Prostate cancer
Gonadotropin Releasing Hormone Analogues (5)
MOA?
– Chronic administration inhibits the release of gonadotropins (FSH & LH)
– Leads to suppression of testicular steroidogenesis due to decreased levels of LH and FSH, and subsequent decrease in testosterone
GnRH - pulsatile can increase FSH or LH and increase testosterone
Given chronically, will decrease secretions
Prostate cancer
Gonadotropin Releasing Hormone Analogues (5)
AE? (2)
– *Transient surge of testosterone secretion: intial actions elevate LH and FSH, need to use with anti-androgen in the first few months
– *Decreased libido
– Hot flash/flush
Prostate cancer
GnRH receptor antagonist
name?
MOA?
Degarelix
– Reversibly binds to GnRH receptors in anterior pituitary to block receptor, decreasing FSH and LH secretion
– Results in rapid androgen deprivation and decrease in testosterone levels
avoids transient surge
Prostate cancer
GnRH receptor antagonist - Dagarelix
AE?
– Hot flash/flush
Prostate cancer
Non-Steroidal Anti-Androgens (5)
– Bicalutamide
– Enzalutamide
– Tlutamide
– Nilutamide
– Cyproterone: steroidal - deriverate of progesterone
Low activity, can compete with testosterone receptors and prevent action
Prostate cancer
Non-Steroidal Anti-Androgens (5)
MOA?
– Inhibit androgen actions by competing with androgens for binding to androgen receptors in target tissue
– Can also be used to control testosterone surge (“flares”) caused by GnRH analogues
