Female Reproductive Pharmacology - Gauthier Flashcards
Recall 3 endogenous human estrogens.
Which is most potent? Least?
Which is derived from testosterone? Androstenedione?
17b-Estradiol, Estrone, Estriol
17b-Estradiol is most potent, Estriol is least (urine metabolite)
Aromatase converts testosterone to 17b-estradiol, and androstenedione to estrone.
Compare and contrast the kinetic properties of estrogens and progestins.
Both are serum protein-binding (estrogens to SHBG/albumin, progestins to CBG/albumin)
Both are metabolized by the liver and have a high first-pass effect.
Presumably, both undergo enterohepatic recirculation.
Compare and contrast the estrogen and progestin receptors.
Two subtypes of either: ERa+ERb/PRa+PRb
A cell membrane receptor for estrogen has been assumed to exist.
There are 8-10 listed physiological effects of estrogen. Try to recall as many as you can.
Feedback regulation of gonadotropin release
Positive effects on bone mass, skeletal maturation, epiphyseal plate closure
Alterations of clotting/fibrinolysis and bile composition
Changes in cervical mucus and endometrium
Enhanced tubal contractility
Lipid profile shift (+TGs, -Chol)
Among the effects of estrogens are “alterations of clotting, fibronolysis, and bile composition”.
Try to better characterize specifically how these are altered.
Inhibition of PAI-1 with a concomitant increase in fibrinogen leads to a prothrombotic state.
Increased cholesterol comoposition and decreased bile acids in bile predisposes to gallstones.
There are 4 listed physiologic effects of progesterone. Try to name all of them.
- Decreases the frequency of GnRH pulses (suppresses gonadotropins)
- Decrease estrogen-drive endometrial proliferation; form a secretory endometrium
- Change cervical mucous to a scant, viscid material
- Maintenance of pregancy
Are estrogens or progestins responsible for each following effect:
- Endometrial hyperplasia
- Thinning of cervical mucus
- Reduction of tubal contractions
- Estrogens
- Estrogens
- Progestins
There are many pharmaceutical preparations of estrogen.
Compare and contrast Ethinyl Estradiol, Mestranol, Estradiol Valerate.
What about equine estrogens?
Ethinyl Estradiol: A 17a-alkylated estrogen that can survive hepatic metabolism (analogous to Stanozolol or Danozol). Potent.
Mestranol: A prodrug of Ethinyl Estradiol (one methyl substitution)
Estradiol Valerate: An ester dissolved in oil and administered intramuscularly.
Equine estrogens derived from mare’s urine consists of weaker estrogen sulfate esters.
There are many other forms of environmental estrogens.
Describe and contrast Genistein, Bisphenol A, Disethylstilbestrol
Genistein is a phytoestrogen classically found in soy (and other stuff)
Bisphenol A is a synthetic compound used in plastics which can trigger estrogenic pathways.
Diethylstilbestrol is a former synthetic estrogen which can cause certain vaginal (and apparently prostate?) cancers.
What therapeutic uses are there for estrogens?
Progestins?
Combination oral contraception, hormone replacement therapy, failure of pituitary function and ovarian development
Hormonal contraception, hormone replacement therapy, diagnosis of secondary amenorrhea & endometrial hyperplasia
Name 5 side effects of estrogens.
- Gallbladder disease
- Thromboembolic disease
- Nausea/vomiting on initial use
- Breast swelling
- Migraine headaches
Who should not receive exogenous estrogens?
Those with:
Pregnancy, estrogen-dependent cancers, undiagnosed uterine bleeding, and thromboembolic disorders
Clomiphene
Indication?
Mechanism of action?
Side effects?
Clomiphene
Induction of ovulation.
Racemic mixture of two isomers, one antagonistic to the estrogen receptor. Inhibits negative feedback to increase LH/FSH release.
Ovarian hyperstimulation, multiple births, hot flashes
Tamoxifen
Indication?
Mechanism of action?
Side effects?
Tamoxifen
Treatment of ER+ breast cancer
SERM; mixed effects but anti-estrogenic in the breast.
Hot flashes, endometrial proliferation, increased thromboembolism, anti-resorptive effect on bone.
Raloxifene
Indication?
Mechanism of action?
Side effects?
Raloxifene
Osteoporosis and risk reduction for invasive breast cancer
SERM; estrogen agonist in bone.
Reduces total cholesterol, hot flashes, increases thrombosis & leg cramps.
Name and distinguish 3 aromatase inhibitors.
What is their indication?
Side effect?
Letrozole & Anastrozole (nonsteroidal reversible inhibitors), Exemestane (steroidal suicide inhibitor)
Treatment of breast cancer (maybe ovulation)
Hot flashes.
There are many pharmaceutical preparations of progestins.
Compare and contrast Medroxyprogesterone, Norethindrone, and Norgestrel.
Medroxyprogesterone: An ester analog that can be taken orally or injected.
Norethindrone: C17 ethiny substitution that allows reduced hepatic metabolism (like ethinyl estraodiol, stanazolol)
Norgestrel: Racemic mixture (active: Levonorgestrel) with less androgenic activity.
What is unique about drospirenone?
What are the consequences of this?
Drospirenone is used as a progestin, but is a spironolactone analogue!
Reduced androgenic effect (can be used to treat acne, PMD)
Watch out for hyperkalemia…
What side effects do most progestins have?
Headache, breakthrough bleeding, and androgenic actions such as acne or hirsutism (not drospirenone!)
Mifepristone
Indication?
Mechanism of action?
Side effects?
Mifepristone
Abortifacient (Note: Add a prostaglandin such as misoprostol)
Competitive progsterone receptor antagonist; causes decidual breakdown and placental detachment, and sensitizes to prostaglandins.
Vaginal bleeding
Ulipristal
Indication?
Mechanism of action?
Side effects?
Ulipristal
Inhibition of ovulation, mostly for emergency contraception.
Partial progesterone receptor agonist, inhibits the LH surge to prevent ovulation.
Headache, abdominal pain
Describe the two conventional hormonal approaches to contraception.
Combined (Estrogen+Progestin)
Progestin alone
Describe three options available for postcoital emergency contraception.
2x dose of CHC (Levonorgestrel + Ethinyl estradiol)
Levonorgestrel alone (better)
Ulipristal
Describe the two approaches to hormone replacement therapy.
Combined (Estrogen + Progestin)
Estrogen only (if uterus is not present)
Estrogens may be used to treat osteoporosis. Name two other drugs that can help.
(okay, the two mentioned in lecture)
Raloxifene, Alendronate.
(yeah yeah, there were many more back in endo)
