Other Endocrine Disorders & Prostate Cancer Flashcards
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
Prostate cancer
Androgen Biosynthesis Inhibitors
name 1
MOA?
Abiraterone
– Selectively inhibits CYP17 (an enzyme expressed in and required for androgen biosynthesis in testicular, adrenal and prostatic tumor tissues
- prevent synthesis of testosterone
Prostate cancer
Androgen Biosynthesis Inhibitors
AE (1)
– Hypertension
– Hypokalemia
– *Peripheral Edema: CYP17 also metabolizes neurocorticoids
- Now we are preventing their breakdown which leads to water rentention and can lead to edema
Alopecia (Hair Loss)
cause?
what is an inhibitor of 5α-reductase
Androgens
– Stimulate hair growth on face, chest, back
– Inhibit hair growth on scalp
Finasteride
– Inhibitor of 5α-reductase (prevents conversion of
testosterone into the more potent dihydrotestosterone)
(most potent forma nd affinity for receptor)
– Applied topically and can take months to produce effects
takes a long time to see effects
Alopecia (Hair Loss)
finasteride adverse effects? (1)
- *reduced libido (impotence)
- tenderness of the breasts
Alopecia (Hair Loss)
another drug for hair loss?
Minoxidil - better for alopecia
▪ Vasodilator originally developed for hypertension
▪ In hair follicles is converted to the more potent
metabolite, minoxidil sulfate
▪ Minoxidil sulfate increases blood supply to hair
follicles, thereby stimulating growth of new hair
- Hair follicle is often resting and not in state to grow more
- Need to shed hair first
- Often initially, there will be noticeable hair loss before growth
describe hirsutism
what can be used to treat it?
Excessive body hair in men and women on parts of
the body where hair is normally absent
Eflornithine - gets rid of hair growth on face
▪ Originally developed as an antiprotozoal agent
▪ Irreversibly inhibits ornithine decarboxylase in hair
follicles to reduce cell replication and the growth of new hair follicles
- Required for formation of polyamines - stabilize DNA during replication
▪ May cause acne
what can prevent menopausal symptoms or osteoporosis?
Low-dose estrogen or estrogen/progestogen
combinations are used as hormonal replacement
therapy
which drugs antagonize actions of GH to treat acromegaly
Pegvisomant (modified GH analogues) or somatostatin analogues (octreotide)
what can be used for male hypogonadism
or female hyposexuality following ovariectomy?
Hormone replacement therapy with testosterone
Prostate cancer can be treated with the following (3)
– GnRH analogues (inhibit FSH/LH secretion with chronic use)
– Non-steroidal anti-androgens
– Abiraterone
Alopecia is treated with the following (3)
– Finasteride
– Eflornithine
– Minoxidil
