Owen 12-14-07 Pharmacology Of Androgens

Front 1

Define Androgens.
Explain the importance of Testosterone.
Describe the synthesis and metabolism of Testosterone.
Explain how Testosterone’s effects may mediated directly or indirectly.
Describe the androgen receptor.
Explain the hormonal control of testicular function.
List examples of synthetic analogues of Testosterone. Contrast these with Testosterone.

Back 1

List unwanted and adverse androgen effects.
List a contraindication to androgen use.
Explain the therapeutic and unapproved uses of Androgenic Steroids.
List the categories of Antiandrogens and representative drugs in each.
List the clinical application of listed antiandrogen drugs and be able to explain how each drug exerts its effect. Also indicate possible problems with the use of these drugs when given.

Front 2

Testosterone – most impt androgen in humans – synthesized by Leydig cells in the testes & in smaller amts by cells in the_____ (female) & by the _______ gland.

Back 2

Testosterone – most impt androgen in humans – synthesized by Leydig cells in the testes & in smaller amts by cells in the ovary (female) & by the adrenal gland.

Front 3

Testosterone:
It stimulates virilization & is an impt ________genic hormone.
In both sexes androgens stimulate body hair growth, positive n_______ balance, bone growth, muscle development & e_________

Back 3

Testosterone:
It stimulates virilization & is an impt spermatogenic hormone.
In both sexes androgens stimulate body hair growth, positive nitrogen balance, bone growth, muscle development & erythropoiesis

Front 4

adult male has ~600 ng/dl of testosterone. How much does adult female have?

Back 4

female: 30-50 ng/dl

Front 5

Cytochrome P450, 19 enzyme complex. What's that?

Back 5

aromatase

Front 6

Look up androgen receptor : Gln 20, Pro 8, Gly 23, binding domain, etc

Back 6

?

Front 7

DHT binds to androgen receptor. What is released?

Back 7

HSP - heat shock protein

look up the rest of the path

Front 8

Gn-RH is released in what fashion?

Back 8

pulsatile

Front 9

LH has its primary effect on what cells?

Back 9

Leydig

Front 10

FSH has primary effect on what cells?

Back 10

Sertoli cells

Front 11

sertoli cells release what protein to negatively feed back to pituitary?

Back 11

inhibin

Front 12

Is ingestion of testosterone an effective means of replacing testosterone deficiency?

Back 12

no

Therefore most pharmaceutical preparations of androgens are designed to bypass hepatic metabolism of testosterone

Front 13

Testosterone cypionate – Esterifying a fatty acid to the 17alpha hydroxyl group of testosterone creates a compound more l________ than testosterone.

Back 13

lipophilic

Front 14

The following are produced by adding an alkyl group on the 17 alpha position of testosterone:
Ox_________
Stan_______
Fluoxy____________

Back 14

The following are produced by adding an alkyl group on the 17 alpha position of testosterone:
Oxandrolone
Stanazolol
Fluoxymesterone

Front 15

Oxandrolone
Stanazolol
Fluoxymesterone
Alkylated androgens such as these are are subject to less hepatic metabolism than testosterone, but cause___________

Back 15

hepatotoxicity

Front 16

Therapeutic Uses of Androgens

Male Senescence - will increase bone mineral density and lean mass and decrease their____ mass.

Back 16

fat

Front 17

Therapeutic Uses of Androgens

Female Hypogonadism – may improve their _____,energy, muscle mass and strength, or bone mineral density

Back 17

libido

Front 18

Unwanted effects of Androgens

Eventual decrease of __________ release, with resultant infertility, and salt and water retention leading to edema. (Decreased spermatogenesis, gynecomastia, testicular atrophy, prostate hypertrophy)

Back 18

Unwanted effects of Androgens

Eventual decrease of gonadotropin release, with resultant infertility, and salt and water retention leading to edema. (Decreased spermatogenesis, gynecomastia, testicular atrophy, prostate hypertrophy)

Front 19

Unwanted effects of Androgens

_____________ of the liver reported.
Impair growth in children (via premature fusion of epiphyses).

Back 19

Unwanted effects of Androgens

Adenocarcinoma of the liver reported.
Impair growth in children (via premature fusion of epiphyses).

Front 20

Unwanted effects of Androgens

Cause a_____
Lead to masculination in girls (h_______, depression of menses and ______ enlargement)

Back 20

Unwanted effects of Androgens

Cause acne
Lead to masculination in girls (hirsutism, depression of menses and clitoral enlargement)

Front 21

Unwanted effects of Androgens

Increased ______ ratio.
Behavioral effects including excessive r___ or hostility.

Back 21

Unwanted effects of Androgens

Increased LDL/HDL ratio.
Behavioral effects including excessive rage or hostility.

Front 22

Androgens modified chemically to alter the balance anabolic and other effects (EX. n_________ – increase protein synthesis & muscle development – used in the therapy of aplastic anemia & abused)

Back 22

nandrolone

Front 23

In both sexes high doses of anabolic steroids can cause cholestatic j________, elevation of liver enzyme levels & possibly hepatocellular c_______ & increased risk of c______ heart disease.

Back 23

In both sexes high doses of anabolic steroids can cause cholestatic jaundice, elevation of liver enzyme levels & possibly hepatocellular carcinoma & increased risk of coronary heart disease.

Front 24

Contraindication to Androgen Use

Back 24

Pregnancy

Front 25

Antiandrogens:
Receptor antagonist examples?

Back 25

Flutamide
Cyproterone

Front 26

5α-reductase inhibitor example?

Back 26

Finasteride

Front 27

Steroid synthesis inhibitor examples?

Back 27

Ketoconazole
Spironolactone

Front 28

Gonadotrophin-releasing analogues examples?

Back 28

Gonadorelin
Leuprolide

Front 29

Flutamide (Eulexin) & Bicalutamide (Casodex)

Nonsteroidal drugs that act as competitive antagonists at the _________ receptor.
Used in combination with a GnRH analogue to treat patients with advanced p------ cancer.
Side effects – Hepatitis & G--------.

Back 29

Flutamide (Eulexin) & Bicalutamide (Casodex)

Nonsteroidal drugs that act as competitive antagonists at the androgen receptor.
Used in combination with a GnRH analogue to treat patients with advanced prostate cancer.
Side effects – Hepatitis & gynecomastia.

Front 30

Cyproterone

Competitive antagonist at androgen receptors.
Used in the treatment of women with__________.

Back 30

Cyproterone

Competitive antagonist at androgen receptors.
Used in the treatment of women with hirsutism.

Front 31

Receptor inhibitors

Flutamide & related drugs - nonsteroidal compounds that act as competitive antagonists at androgen receptors. Used to decrease the action of endogenous androgens in patients withp_______ carcinoma.
Spironolactone, drug use principally as a potassium-sparing diuretic, also inhibits androgen receptors & is used in the treatment of h________.

Back 31

Receptor inhibitors

Flutamide & related drugs - nonsteroidal compounds that act as competitive antagonists at androgen receptors. Used to decrease the action of endogenous androgens in patients with prostate carcinoma.
Spironolactone, drug use principally as a potassium-sparing diuretic, also inhibits androgen receptors & is used in the treatment of hirsutism.

Front 32

Finasteride (Proscar, Propecia)

5α-Reductase is an enzyme responsible for the conversion of testosterone to dihydrotestosterone (DHT). Cells of the prostate are stimulated to grow by DHT. Finasteride inhibits this enzyme and thus reduces cell proliferation in the prostate.
Used for benign prostatic hyperplasia (BPH)
Propecia is used to treat hair loss.
Side effects – _____________, ______________

Back 32

Finasteride (Proscar, Propecia)

5α-Reductase is an enzyme responsible for the conversion of testosterone to dihydrotestosterone (DHT). Cells of the prostate are stimulated to grow by DHT. Finasteride inhibits this enzyme and thus reduces cell proliferation in the prostate.
Used for benign prostatic hyperplasia (BPH)
Propecia is used to treat hair loss.
Side effects – Loss of libido, erectile dysfunction.

Front 33

5α-Reductase Inhibitors

Testosterone is converted to DHT by the enzyme ___________. Some tissues, most notably prostate cells & hair follicles depend on DHT rather than testosterone for androgenic stimulation. This enzyme is inhibited by finasteride, a drug used to treat benign prostatic hyperplasia &, at a lower dose, to prevent hair loss in men. Because the drug does not interfere with the action of testosterone, it is less likely than other antiandrogens to cause i____________, i_________ & loss of libido

Back 33

5α-Reductase Inhibitors

Testosterone is converted to DHT by the enzyme 5α-reductase. Some tissues, most notably prostate cells & hair follicles depend on DHT rather than testosterone for androgenic stimulation. This enzyme is inhibited by finasteride, a drug used to treat benign prostatic hyperplasia &, at a lower dose, to prevent hair loss in men. Because the drug does not interfere with the action of testosterone, it is less likely than other antiandrogens to cause impotence, infertility & loss of libido

Front 34

Ketoconazole

Ant______ drug – It inhibits several of the cytochrome P-450 enzymes involved in steroid synthesis

Back 34

Ketoconazole

Antifungal drug – It inhibits several of the cytochrome P-450 enzymes involved in steroid synthesis

Front 35

Inhibitors of Steroid Synthesis

Ketoconazole, an antifungal agent, inhibits gonadal and adrenal steroid synthesis. The drug has been used to suppress adrenal _______ synthesis in patients with steroid-responsive metastatic tumors. Part of the antiandrogen effect of spironolactone is due to reduction in ____________, an enzyme that participates in androgen synthesis.

Back 35

Inhibitors of Steroid Synthesis

Ketoconazole, an antifungal agent, inhibits gonadal and adrenal steroid synthesis. The drug has been used to suppress adrenal steroid synthesis in patients with steroid-responsive metastatic tumors. Part of the antiandrogen effect of spironolactone is due to reduction in 17α-reductase, an enzyme that participates in androgen synthesis.

Front 36

Gonadorelin (Factrel)

Synthetic GnRH analogue
For stimulation of gonadotropins (when given in _________ form) or suppression of gonadotropins when given in __________ form.
Suppression therapy – used in the treatment of endo_________, prostate cancer, and central precocious puberty.
Stimulation therapy is mainly for hypogonadotropic hypogonadism.
Leu______, go_______ & na_______ are also synthetic GnRH analogues.

Back 36

Gonadorelin (Factrel)

Synthetic GnRH analogue
For stimulation of gonadotropins (when given in pulsatile form) or suppression of gonadotropins when given in continuous form.
Suppression therapy – used in the treatment of endometriosis, prostate cancer, and central precocious puberty.
Stimulation therapy is mainly for hypogonadotropic hypogonadism.
Leuprolide, goserelin & nafarelin are also synthetic GnRH analogues.

Front 37

Gonadotropin-releasing hormone analogs

Reduction of gonadotropins, esp __, reduces the production of testosterone. This can be effectively accomplished with long-acting depot preparations of L________ or similar gonadotropin-releasing hormone agonists. [Steady dosing inhibits gonadotropin release by causing down regulation of GnRH receptors in pituitary cells that normally release gonadotropins.] These analogs used in prostatic carcinoma. During the 1st week of therapy, an androgen receptor antagonist (eg. F_________) is added to prevent the tumor flare that can result from the surge in Testosterone synthesis caused by the initial agonistic action of the GnRH agonist. Within several weeks, testosterone production falls to normal & then below normal.

Back 37

Gonadotropin-releasing hormone analogs

Reduction of gonadotropins, esp LH, reduces the production of testosterone. This can be effectively accomplished with long-acting depot preparations of Leuprolide or similar gonadotropin-releasing hormone agonists. [Steady dosing inhibits gonadotropin release by causing down regulation of GnRH receptors in pituitary cells that normally release gonadotropins.] These analogs used in prostatic carcinoma. During the 1st week of therapy, an androgen receptor antagonist (eg. Flutamide) is added to prevent the tumor flare that can result from the surge in Testosterone synthesis caused by the initial agonistic action of the GnRH agonist. Within several weeks, testosterone production falls to normal & then below normal.

Front 38

Combined hormonal contraceptives:

Exert an antiandrogenic effect when they are used in women with h__________ resulting from excess production of androgenic steroids. The estrogen in the contraceptive acts in the liver to increase the production of SHBG (____ _____ ______ ______ _____), which in turn acts to reduce the conc of free androgen in the blood.

Back 38

Combined hormonal contraceptives:

Exert an antiandrogenic effect when they are used in women with hirsutism resulting from excess production of androgenic steroids. The estrogen in the contraceptive acts in the liver to increase the production of SHBG (Sex hormone binding globulin), which in turn acts to reduce the conc of free androgen in the blood.