ANDROGENS pharmacology

What are some of the physiological effects of androgens?

- Physiological effects: Necessary for secondary sex characteristics (facial hair)

health and maintenance of genital organs (penis, scrotum, testes [primary source for testosterone once a male is mature]),

spermatogenesis, erectile response,

bone growth lengthwise (in combination with growth hormone),
impacts vocal cords and deepens voice,
increase skeletal muscle mass,
increase libido.

How can testosterone deficiency be treated?

HRT --> Giving extra T.

What is the nature of the classical androgen receptor (AR)? Is it a cell surface receptor?

No, it is cytoplasmic/nuclear receptor and acts via a genomic mechanism (activates gene expression)!

What portion of DNA will hormone-bound receptor dimers bind to?

Androgen Response Element

What is the role of RNA pol II in gene expression?

To make mRNA from a DNA template..

Does the transcriptional machinery produce mRNA via the process of transcription?

Are many genes activated by androgens?

YES.

YES. (for example, genes involved in skeletal muscle development; genes involved in sexual activity).

What is the nature of the membrane androgen receptor (mAR)?

The mAR is a newly discovered membrane bound cell surface GPCR that responds to androgens and increases cAMP and PKA activity. It acts via a non-genomic mechanism

What are the two active metabolites of testosterone?

Estradiol/DHT

What are the names of the enzymes that produce these respective active metabolites? (estradiol/dht)

Aromatase / 5-alpha reductase

In which tissues is 5 alpha reductase abundantly expressed in males? How about in females?

males - skin, prostate, penis/scrotum, bone

females - skin/bone

In which tissues is aromatase abundantly expressed in females? How about in males ?

females- adipose/ovaries

males - adipose

As the levels of testosterone within the male patient increases, what happens to the levels of estradiol, and Dihydrotestosterone?

Estradiol? Increase

Dihydrotestosterone? Increase

How does the increases of testosterone relate to the possible adverse effects of gynecomastia and benign prostatic hyperplasia?

BPH - Directly, more estrogen causes gynecomastia and DHT causes prostatic hyperplasia

Draw the structure of testosterone. Circle the 17 carbon. Are the 17alpha alkylated analogs of testosterone more or less susceptible than testosterone itself to first-pass metabolism after oral administration? Do these types of testosterone analogs exhibit potential hepatotoxicity? Do they show reduced androgenicity with respect to testosterone? How is methyltestosterone administered? Fluoxymestrone?

(Less susceptible to metabolism, but higher risk of hepatotoxicity. Less androgenicity. Methyltestosterone/Fluoxymestrone is PO)

Transdermal delivery of testosterone via gel administration can be achieved using which formulation?

Androgel

Why does androgen replacement therapy exhibit potential adverse effects such as breast tenderness and gynecomastia in men?

Excess androgen gets converted into estrogens.

In addition to those listed in class, please note what else is a AE with long term androgen use

use of androgens may also be associated with adverse behavioral effects (e.g increased aggressiveness, irritability)- aka. ROID RAGE.
This was not mentioned in class. Especially pertinent to people who abuse androgens for bodybuilding purposes.

Increase LDL, decreased HDL, and risk of clots, testicular atrophy, increased sebum synthesis, hirsutism, hepatotoxicity, BPH risk, prostate cancer risk.

List several adverse effects associated with long term use of androgens.

Increase LDL, decreased HDL, and risk of clots, testicular atrophy, increased sebum synthesis, hirsutism, hepatotoxicity, BPH risk, prostate cancer risk.

List 3 competitive antagonists of the androgen receptor and their uses.

Cyproterone/Spironolactone --> Hirsuitism Tx.
Flutamide --> Prostate Cancer
Drospirone --> Antiandrogenic Progestin

What is gossypol? What is its mechanism of action?

Male contraceptive, injures seminiferous epithelium aka spermatotoxicant.

What is leuprolide and how is it does in males with prostate cancer?

GnRH analogue which suppresses LH release.

Why is it effective in slowing the prostate cancer growth?

Prevents androgen synthesis for AR+ tumors.