Male Reproductive Pharmacology - Gauthier

Question 1

What effects do testosterone, dihydrotestosterone, and estradiol each facilitate?

Answer 1

Testosterone: Maturation of internal genitalia, skeletal muscle anabolism, erythropoiesis.

Dihydrotestosterone: Maturation of external genitalia, hair, and prostatic hyperplasia.

Estradiol: Epiphyseal closure, bone density, and libido (including in men!)

Question 2

What is the common precursor to dihydrotestosterone and estradiol?

What enzymes catalyze their production? Where in men?

Answer 2

Both synthesized from testosterone.

Dihydrotestosterone made using 5a-reductase (two isoforms, one in skin/liver/bone, two in urogenital tissue)

Estradiol made using aromatase (sertoli cells)

Question 3

Testosterone has poor oral metabolism due to a high first-pass effect. How is this overcome?

Answer 3

By parenteral administration: patches, gels, buccal tablets, injection (eg Cypionate)

17a-alkylation (eg Stanozolol)

Question 4

What is the longest lasting androgen analog?

What is the longest lasting PDE5 inhibitor?

Answer 4

Cypionate (fatty ester lasts for days-weeks)

Tadalafil (36hr effect, “the weekend drug”)

Question 5

What is the chief application for androgens?

Try to name 5-6 other indications.

Answer 5

Male hypogonadism / Testosterone replacement therapy

Male sensescence, testosterone deficiency in women, blood dyscrasias, angioedema, endometriosis/fibrocystic breast disease. Abused by athletes.

Question 6

Describe the structure and kinetics of Stanozolol.

What are its unique side effects?

What other drug mimics this behavior? Does it have any specific indications?

Answer 6

Stanozolol is a 17a-alkylated testosterone. The substitution reduces hepatic catabolism, so it can be taken orally.

It can cause hepatotoxicity (cholestatsis, blood-filled hepatic cysts) and decreased HDL in large doses.

Danazol is also 17a-alkylated. It is mentioned specifically for treatment of blood dyscrasias, endometriosis, fibrocystic breast disease, and hereditary angioedema.

Question 7

A certain subtype of angioedema can be treated by 17-alkylated androgens. Can you explain what subtype and its cause?

Name two 17-alkylated androgens.

Answer 7

Hereditary angioedema (resulting from deficiency of C1 esterase inhibitor deficiency)

Stanozolol, danazol

Question 8

Describe the abuse of androgens by athletes

(which ones, benefits, but not side effects)

Answer 8

Testosterones are used for their anabolic effects on skeletal muscle and erythropoiesis.

Testosterone is most popular, followed by nandrolone (an ester) and stanozolol. Recently, tetrahydrogestinone (THG) was developed to avoid detection. Androstenedione and DHEA have been available as diet supplements.

Question 9

There are perhaps 10 adverse effects caused by androgen use. Try to name as many as you can.

Answer 9

Suppressed fertility and testicular size (inhibited gonadotropins)

Erythrocytosis

Gynecomastia

Hepatotoxicity, lipid profile alteration

Phallic & clitoral enlargement

Stunting of linear growth

Psychological disorders

Cardiac disease - Notably in senescent men

Acne, more aggressive sexual behavior

Question 10

Which class of androgens avoids gynecomastia?

Which class of androgens causes hepatotoxicity?

How can linear growth stunting be avoided?

Answer 10

Those with A-ring modifications (eg DHT)

17a-alkylates (eg Stanozolol, danazol)

In hypogonad children, precede androgen therapy with growth hormone replacement until height is restored.

Question 11

Leuprolide

What is the mechanism of action?

Indications?

Side effects?

Answer 11

Leuprolide

Reduces testosterone production by downregulating the GnRH receptor (initial spike!)

Advanced prostate cancer, endometriosis, central precocious puberty.

Hot flashes, decreased bone density, vaginal dryness/atrophy, erectile dysfunction.

Question 12

Flutamide

What is the mechanism of action?

Indications?

Side effects?

Answer 12

Flutamide

Reversible, competitive inhibition of the androgen receptor.

Metastatic prostate cancer, female hirsutism

Galactorrhea, breast tenderness, gynecomastia, hot flashes, impotence, decreased libido, tumor flare. Hepatic failure!

Question 13

Finasteride

What is the mechanism of action?

Indications?

Side effects?

Answer 13

Finasteride

5a-reductase antagonist

Benign prostatic hyperplasia and treatment of male pattern baldness.

Impotence, decreased libido.

Question 14

What drug should flutamide be coadministered with?

Is it steroidal or nonsteroidal?

Which isoform of 5a-reductase is inhibited by finasteride?

Answer 14

Since it is weak, use in conjunction with GnRH analog like leuprolide.

Nonsteroidal (recall that androgen antagonists are steroidal eg Megestrol, or nonsteroidal eg Flutamide)

Type II.

Question 15

What do you suppose the side effects of most antiandrogens are due to?

Answer 15

(conjecture) Many of these appear to be the effect of increased prolactin, as loss of sex hormones should reduce negative feedback.

(note galactorrhea, erectile dysfunction, gynecomastia…)

Question 16

Describe the normal control of penile tumescence (erection).

Answer 16

The helicine arteries, under influence by PNS or endothelial cell NO, activate GC >> cGMP to relax and increase blood flow (engorgement).

This is reversed by the action of PDE-5, which degrades cGMP.

Question 17

Alprostadil

What is the mechanism of action?

Indications? Formulations?

Side effects?

Answer 17

Alprostadil

PGE1 analog, causes dilation of cavernosal arteries.

For erectile dysfunction, given as intracavernous injection or urethral suppository for 1-3hr tumescence.

Penile pain & urethral burning (ya think?)

Question 18

Name 3 PDE-5 inhibitors.

What are their indications?

Answer 18

Sildenafil (viagra), Tadalafil (cialis), vardenafil.

For erectile dysfunction; sildenafil approved for pulmonary hypertension!

Question 19

What are the side effects of PDE5 inhibitors?

What are these mostly due to?

Answer 19

Headache, flushing, dyspepsia, back pain, visual disturbances.

Other phosphodiesterases may be inhibited (eg PDE-3 in vascular tissue, PDE-6 in photoreceptors)

Question 20

Mr. R, a 76-yo man on nitroglycerin, reports to the ER with massive hypotension, onset during earlier sexual intercourse.

What is to blame? How does this occur?

Answer 20

Mr. R had taken a PDE-5 inhibitor such as Sildenafil, which potentiates the vasodilatory effect of nitrates (nitroglycerin donates NO, sildenafil keeps its downstream effect from attenuating). This resulted in his massive hypotension.