Reproductive Pharmacology

Question 1

Leuprolide

Answer 1

Mech: GnRH analog with agonist properties when used in pulsatile fashion; antagonist properties when used in continuous fashion (down regulates GnRH receptor in pituitary –> decreased FSH/LH)

Clinical use: Infertility (pulsatile), prostate cancer (continuous, use with flutamide), uterine fibroids (continuous), precocious puberty (continuous)

Toxicity: Antiandrogen, nausea, vomiting

Question 2

Testosterone, methyltestosterone

Answer 2

Mech: Agonist at androgen receptors

Clinical use: Treats hypogonadism and promotes development of secondary sex characteristics; stimulation of anabolism to promote recovery after burn or injury

Toxicity: causes masculinization in females; reduces intratesticular testosterone in males by inhibiting release of LH (via negative feedback), leading to gonadal atrophy. Premature closure of epiphyseal plates. Increases LDH, Decreases HDL

Question 3

Finasteride

Answer 3

A 5-alpha reductase inhibitor (decreased conversion of testosterone to DHT). Useful in BPH. Also promotes hair growth–used to treat male pattern baldness

Question 4

Flutamide

Answer 4

A nonsteroidal competitive inhibitor of androgens at the testosterone receptor. Used in prostate carcinoma

Question 5

Ketoconazole

Answer 5

Inhibits steroid synthesis (inhibits 17,20-desmolase)

Used to treat PCOS to prevent hirsutism

Toxicity: gynecomastia, amenorrhea

Question 6

Spironolactone

Answer 6

Inhibits steroid binding

Used to treat PCOS to prevent hirsutism

Toxicity: gynecomastia, amenorrhea

Question 7

Estrogens (ethinyl estradiol, DES, mestranol)

Answer 7

Mech: bind estrogen receptors

Clinical use: Hypogonadism or ovarian failure, menstrual abnormalities, HRT in posmenopausal some; 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 positive breast cancer, history of DVTs

Question 8

Clomiphene

Answer 8

SERMs (selective estrogen receptor modulators)

Partial agonist at estrogen receptors in hypothalamus. Prevents normal feedback inhibition and increased release of LH and FSH from pituitary, which stimulates ovulation. Used to treat infertility and PCOS. May cause hot flashes, ovarian enlargement, multiple simultaneous pregnancies, and visual disturbances

Question 9

Tamoxifen

Answer 9

SERM

Antagonist on breast tissue; used to treat and prevent recurrence of ER-positive breast cancer

Question 10

Raloxifene

Answer 10

Agonist on bone; reduces resorption of bone; used to treat osteoporosis

Question 11

Hormone replacement therapy

Answer 11

Used for relief or prevention of menopausal symptoms (e.g. hot flashes, vaginal atrophy) and osteoporosis (increased estrogen, decreased osteoclast activity)

Unopposed estrogen replacement therapy (ERT): increased risk of endometrial cancer, so progesterone is added. Possible increased CV risk

Question 12

Anastrozole/exemestane

Answer 12

aromatase inhibitors used in postmenopausal women with breast cancer

Question 13

Progestins

Answer 13

Mechanism: Bind progesterone receptors, reduce growth and increased vascularization of endometrium

Clinical use: used in oral contraceptives and in the treatment of endometrial cancer and abnormal uterine bleeding

Question 14

Mifepristone (RU-486)

Answer 14

Mech: 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 15

Oral contraception (synthetic progestins, estrogen)

Answer 15

Estrogen and progestins inhibit LH/FSH and thus prevent estrogen surge. No estrogen surge –> no LH surge –> 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

Contraindications: smokers >35 years of age (increased risk of CV events), pts with history of thromboembolism and stroke or history of estrogen-dependent tumor

Question 16

Terbutaline

Answer 16

Beta2 agonist that relaxes the uterus; reduces premature uterine contractions

Question 17

Tamsulosin

Answer 17

Alpha-1 antagonist that is used to treat BPH by inhibiting smooth muscle contraction. Selective for alpha1A, D receptors (found on prostate) vs vascular alpha1B receptors

Question 18

Sildenafil, vardenafil

Answer 18

Mech: Inhibit PDE5, causing increase in cAMP, smooth muscle relaxation in the corpus caverosum, increased blood flow, penile erection

Clinical use: Treatment of ED

Toxicity: Headache, Heartburn, Hypotension:
- headache, flushing, dyspepsia, impaired blue-green color vision. Risk of life-threatening hypotension in patients taking nitrates

Question 19

Danazol

Answer 19

Mech: synthetic androgen that acts as partial agonist at androgen receipts

Clinical use: Endometriosis, hereditary angioedema

Toxicity: Weight gain, edema, acne, hirsutism, masculinization, decreased HDL levels, hepatotoxicity