Reproductive - Pharmacology

Question 1

Control of reproductive hormones (589)

Answer 1

Question 2

Leuprolide

• Mechanism
• Clinical use
• Toxicity

Answer 2

• Mechanism
  
  • GnRH analog with agonist properties when used in pulsatile fashion
  • Antagonist properties when used in continuous fashion (downregulates GnRH receptor in pituitary –>Ž decreased FSH/LH).
  • Leuprolide can be used in lieu of GnRH.
• Clinical use
  
  • Infertility (pulsatile), prostate cancer (continuous—use with flutamide), uterine fibroids (continuous), precocious puberty (continuous).
• Toxicity
  
  • Antiandrogen, nausea, vomiting.

Question 3

Estrogens

• Examples
• Mechanism
• Clinical use
• Toxicity

Answer 3

• Examples
  
  • Ethinyl estradiol, DES, mestranol
• Mechanism
  
  • Bind estrogen receptors.
• Clinical use
  
  • Hypogonadism or ovarian failure, menstrual abnormalities, HRT in postmenopausal women
  • Use in men with androgen-dependent prostate cancer.
• Toxicity
  
  • Increased risk of endometrial cancer, bleeding in postmenopausal women, clear cell adenocarcinoma of vagina in females exposed to DES in utero, increased risk of thrombi.
  • Contraindications—ER (+) breast cancer, history of DVTs.

Question 4

Clomiphene

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 4

• Type of drug
  
  • Selective estrogen receptor modulator—SERM
• Mechanism
  
  • Antagonist at estrogen receptors in hypothalamus.
  • Prevents normal feedback inhibition and increases release of LH and FSH from pituitary, which stimulates ovulation
• Clinical use
  
  • Used to treat infertility due to anovulation (e.g., PCOS).
• Toxicity
  
  • May cause hot flashes, ovarian enlargement, multiple simultaneous pregnancies, and visual disturbances.

Question 5

Tamoxifen

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 5

• Type of drug
  
  • Selective estrogen receptor modulator—SERM
• Mechanism
  
  • Antagonist on breast tissue
  • Agonist at uterus, bone
• Clinical use
  
  • Primarily used to treat and prevent recurrence of ER (+) breast cancer.
• Toxicity
  
  • Associated with endometrial cancer, thromboembolic events.

Question 6

Raloxifene

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 6

• Type of drug
  
  • Selective estrogen receptor modulator—SERM
• Mechanism
  
  • Agonist on bone
  • Antagonist at uterus
  • Decreases resorption of bone
• Clinical use
  
  • Used to treat osteoporosis.
• Toxicity
  
  • Increases risk of thromboembolic events

Question 7

Hormone replacement therapy

• Clinical use
• Toxicity

Answer 7

• Clinical use
  
  • Relief or prevention of menopausal symptoms (e.g., hot flashes, vaginal atrophy)
  • Osteoporosis (increases estrogen, decreases osteoclast activity).
• Toxicity
  
  • Unopposed estrogen replacement therapy (ERT) increases the risk of endometrial cancer, so progesterone is added.
  • Possible increased cardiovascular risk.

Question 8

Anastrozole / exemestane

Answer 8

• Aromatase inhibitors used in postmenopausal women with breast cancer.

Question 9

Progestins

• Mechanism
• Clinical use

Answer 9

• Mechanism
  
  • Bind progesterone receptors
  • Decreases growth
  • Increases vascularization of endometrium.
• Clinical use
  
  • Used in oral contraceptives and in the treatment of endometrial cancer and abnormal uterine bleeding.

Question 10

Mifepristone (RU-486)

• Mechanism
• Clinical use
• Toxicity

Answer 10

• Mechanism
  
  • Competitive inhibitor of progestins at progesterone receptors.
• Clinical use
  
  • Termination of pregnancy.
  • Administered with misoprostol (PGE1).
• Toxicity
  
  • Heavy bleeding, GI effects (nausea, vomiting, anorexia), abdominal pain.

Question 11

Oral contraception (synthetic progestins, estrogen)

• Mechanism
• Toxicity

Answer 11

• Mechanism
  
  • Estrogen and progestins inhibit LH/FSH and thus prevent estrogen surge.
  • No estrogen surge –>Ž no LH surge Ž–> no ovulation.
  • Progestins cause thickening of the cervical mucus, thereby limiting access of sperm to uterus.
  • Progestins also inhibit endometrial proliferation, thus making endometrium less suitable for the implantation of an embryo.
• Toxicity
  
  • Contraindications—smokers > 35 years old (increased risk of cardiovascular events), patients with history of thromboembolism and stroke or history of estrogen-dependent tumor.

Question 12

Terbutaline

• Mechanism
• Clinical use

Answer 12

• Mechanism
  
  • β2-agonist that relaxes the uterus
• Clinical use
  
  • Used to decrease contraction frequency in women during labor.

Question 13

Danazol

• Mechanism
• Clinical use
• Toxicity

Answer 13

• Mechanism
  
  • Synthetic androgen that acts as partial agonist at androgen receptors.
• Clinical use
  
  • Endometriosis and hereditary angioedema.
• Toxicity
  
  • Weight gain, edema, acne, hirsutism, masculinization, decreased HDL levels, hepatotoxicity.

Question 14

Testosterone, methyltestosterone

• Mechanism
• Clinical use
• Toxicity

Answer 14

• Mechanism
  
  • Agonist at androgen receptors.
• Clinical use
  
  • Treats hypogonadism and promotes development of 2° sex characteristics
  • Stimulation of anabolism to promote recovery after burn or injury.
• Toxicity
  
  • Causes masculinization in females
  • Decreased intratesticular testosterone in males by inhibiting release of LH (via negative feedback) –>Ž gonadal atrophy.
  • Premature closure of epiphyseal plates. 
  • Increased LDL, decreased HDL.

Question 15

Antiandrogens:
Mechanism

Answer 15

• Testosterone –> [5α-reductase] –> DHT (more potent).

Question 16

Finasteride

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 16

• Type of drug
  
  • Antiandrogen
• Mechanism
  
  • A 5α-reductase inhibitor (decreases conversion of testosterone to DHT).
  • Promotes hair growth
• Clinical use
  
  • Useful in BPH.
  • Used to treat malepattern baldness.
• Toxicity
  
  • To prevent male-pattern hair loss, give a drug that will encourage female breast growth.

Question 17

Flutamide

• Type of drug
• Mechanism
• Clinical use

Answer 17

• Type of drug
  
  • Antiandrogen
• Mechanism
  
  • A nonsteroidal competitive inhibitor of androgens at the testosterone receptor
• Clinical use
  
  • Used in prostate carcinoma.

Question 18

Ketoconazole

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 18

• Type of drug
  
  • Antiandrogen
• Mechanism
  
  • Inhibits steroid synthesis (inhibits 17,20-desmolase).
• Clinical use
  
  • Used in the treatment of polycystic ovarian syndrome to prevent hirsutism.
• Toxicity
  
  • Gynecomastia and amenorrhea

Question 19

Spironolactone

• Type of drug
• Mechanism
• Clinical use
• Toxicity

Answer 19

• Type of drug
  
  • Antiandrogen
• Mechanism
  
  • Inhibits steroid binding, 17α-hydroxylase, and 17,20-desmolase.
• Clinical use
  
  • Used in the treatment of polycystic ovarian syndrome to prevent hirsutism.
• Toxicity
  
  • Gynecomastia and amenorrhea

Question 20

Tamsulosin

• Mechanism
• Clinical use

Answer 20

• Mechanism
  
  • α1-antagonist
  • Selective for α1A,D receptors (found on prostate) vs. vascular α1B receptors.
• Clinical use
  
  • Used to treat BPH by inhibiting smooth muscle contraction

Question 21

Sildenafil, vardenafil

• Mechanism
• Clinical use
• Toxicity

Answer 21

• Mechanism
  
  • Inhibit phosphodiesterase 5, causing increased cGMP, smooth muscle relaxation in the corpus cavernosum, increased blood flow, and penile erection.
  • Sildenafil** and vardenafil fill the penis.**
• Clinical use
  
  • Treatment of erectile dysfunction.
• Toxicity
  
  • Headache, flushing, dyspepsia, impaired blue-green color vision.
  • Risk of life-threatening hypotension in patients taking nitrates.
  • “Hot and sweaty,” but then Headache, Heartburn, Hypotension.