EXAM #5: ANDROGENS, ANTIANDROGENS, ED Flashcards
Where is Testosterone synthesized?
1) Leydig cells of the Testes (de novo)
2) Adrenal cortex (low potency androgens that get converted)
What does the hypothalamus produce in the synthetic pathway of the androgens?
GnRH
What does they pituitary produce in the synthetic pathway of the androgens?
LH and FSH
What is the function of LH?
1) LH binds Leydig cells in testes
2) Induces the production and secretion of testosterone
3) Testosterone diffuses into the Sertoli cells
What is the function of Testosterone in the Sertoli cells?
Stimulation of spermatogenesis
What is the function of FSH?
- Induces the synthesis of Androgen Binding Protein (ABP) by Sertoli cells
- ABP concentrates Testosterone at the site of spermatogenesis in the Sertoli cells
Describe Testosterone’s feedback in the HPA axis.
Testosterone directly inhibits:
1) LSH and FSH from pituitary
2) GnRH from hypothalamus
What is the function of 17a-hydroxylase in the synthesis of the androgens?
Converts androstenedione to testosterone
What is the function of 5a-reductase in the synthesis of androgens?
Converts testosterone to DHT
*Note that DHT will inhibit the secretion of GnRH and LH
What are the two general effects of the androgens?
1) Androgenic
2) Metabolic effects
What are the “androgenic” effects of the androgens?
- Growth/ development of male reproductive tract
- Male secondary sex characteristics
What are the metabolic effects of the androgens?
Actions on non-reproductive tissue e.g.
- Muscle growth
- Liver production of serum proteins
- Kidney, stimulates EPO
- Bone growth
- Bone marrow stem cell production
What are the three therapeutic androgen preparations?
Methyltestosterone
Testosterone enanthate
Testosterone
What is the problem with oral Testosterone? How is this combated?
Low bioavailability b/c it undergoes extensive first pass metabolism
Administered topically in a gel or transdermal patch
Structurally, how does Testosterone Enanthate differ from Testosterone?
Fatty acid conjugated to Testosterone via an ESTER bond
How is Testosterone Enanthate administered?
Dissolved in oil and administered IM
What is the colloquial name for 17-alkylated derivatives of Testosterone?
Anabolic steroids
This was an attempt to make a drug with METABOLIC effects and without androgenic effects
What is the hallmark 17-alkyated testosterone derivative?
Methyltestosterone
How is Methyltestosterone administered?
Orally, undergoes less first pass metabolism than Testosterone
What adverse effects are associated with androgen therapy?
- Reduction in spermatogenesis and testis size
- Acne
- Polycythemia
- Prostatic enlargement
- Na+/ H20 retention–> HTN
- Increased LDL and decrease HDL–>atherosclerosis
- Mood swings, depression, aggression
What is the theraputic use of antiandrogens in females?
Hirsutism
What are the therapeutic uses for antiandrogens in males?
1) Percocious puberty
2) BPH
3) Prostate cancer
4) Alopecia
What are the androgen receptors antagonists?
Flutamide and Biclatumide
What is the MOA of the androgen receptor antagonists?
Competitive antagonists of the androgen receptor
What is the clinical indication for the androgen receptor antagonists?
Prostate cancer
What toxicities are associated with the androgen receptor antagonists?
- Gynecomastia
- Mild liver toxicity
What drugs are commonly added to Flutamide and Biclatumide therapy? Why?
Androgen receptor blockade increases LH secretion from the pituitary gland; thus, increase Testosterone
Given with a GnRH analog
What is the MOA of Enzalutamide?
Competitive androgen receptor antagonist that ALSO:
1) Inhibits nuclear translocation of the androgen receptor
2) Blocks DNA binding
3) Blocks transcriptional coactivator recruitment
List the GnRH agonists.
Leuprolide
Goserelin
What are the clinical indications for GnRH agonists?
Prostate cancer
What is the MOA of the GnRH agonists?
Constantly elevated GnRH:
1) Desesitizes receptors on pituitary gonadotrophs
2) Decreases LH production and secretion
3) Decreases Testosterone
What is the major adverse effect of GnRH agonists in the treatment of prostate cancer?
Testosterone surge that can cause growth of the cancer
How is the Testosterone surge with GnRH agonists prevented in the treatment of prostate cancer?
AR receptor antagonist coadministration (Flutamide or Bicalutamide)
What is the hallmark GnRH antagonist?
Degarelix
What are the advantages of Degarelix in the treatment of prostate cancer?
1) Faster onset
2) No LH/ Testosterone surge
What class of drug is Abiraterone?
Androgen biosynthetic inhibitor
What is the clinical indication for Abiraterone?
Metastatic prostate cancer
What is the MOA of Abiraterone?
Inhibits 17a-hydroxylase
List the 5a-reductase inhibitors.
Finasteride
Dutasteride
What are the clinical indications for 5a-reductase inhibitors?
BPH
Alopecia
How do 5a-reductase inhibitors treat alopecia?
- High DHT is thought to cause alopecia by inducing apoptosis of dermal papilla
- 5a-reductase inhibitors prevent formation of DHT from Testosterone
What are the adverse effects associated with the 5a-reductase inhibitors?
1) Impotence
2) Gynecomastia
3) LOWER PSA levels leading to FALSE NEGATIVE testing
What is the function of PDE-5 in the penile erection?
Converts cGMP to 5’GMP
cGMP is needed for smooth muscle relaxation and erection
List the PDE-5 inhibitors. What are these drugs clinically indicated for?
Sildenafil
Vardenafil
Tadalafil
1) ED
2) Pulmonary arterial HTN
How does Tadalafil differ from SIldenafil and Vardenafil?
- Double the time to peak concentration
- Half-life of 18 hours
What is a contraindication of PDE-5 inhibitors?
HIV protease inhibitors and Nitrates (can lead to hypotension)
*CYP 3A4 effects INCREASE efficacy of PDE-5
What adverse effects are associated with PDE-5 inhibitors?
1) Cardiac events
2) Priapism
3) Sudden vision loss (blood flow to optic nerve blocked)
