Female Reproductive Pharmacology Flashcards
What are the 3 major estrogens?
Estradiol-17ß
Estrone
Estriol
_______ is the most potent estrogen.
_______ exists in equilibrium w/ estradiol.
_______ has minimal estrogenic activity.
Estradiol-17ß
Estrone
Estriol
Estrogens are normally bound to _____ & ______.
SSBG
**Albumin **
Estradiol undergoes what kind of biotransformation?
Estrogens undergo ________ recirculation.
-
Hepatic biotransformation
- Estradiol –> Estrone –> Estriol
- Estriol = major urinary metabolite
- Enterohepatic circulation
What are the 2 types of nuclear estrogen receptors?
How are they activated?
What is their mechanism of action?
- ER-α & ER-ß
- Ligand-activated transcription factors
- Increase/decrease transcription of target genes
- Multiple mRNA isoforms (promoters & alternative splicing)
- Ligand mediated ER conformation
What are the physiological effects of estrogen on the skeletal system?
- Enhances skeletal maturation & epiphyseal growth plate closure to limit linear growth
- effects on bone mass
- Decrease # & activity of osteoclasts
- effects on bone mass
Estrogen is responsible for feedback regulation of ___________ release.
Gonadotropin
What are the physiological effects of estrogen on lipid metabolism?
- Slightly elevates serum TGs & slightly reduces total serum cholesterol levels
- Increase HDL
- Decrease LDL & LPA
How does estrogen affect the clotting cascade?
-
Increase coagulation factors
- II, VII, IX, X, XII
-
Decrease anticoagulation factors
- Protein C, Protein S, Antithrombin III
- Decreased PAI-1 protein –> increase in fibrinolysis
- Increase both coagulation & fibrinolytic pathways
- Imbalance = adverse effects
How does estrogen affect cholesterol & bile acid secretion?
- Increase cholesterol secretion
- Decrease bile acid secretion
- Increased saturation of bile w/ cholesterol
- Basis for increased gallstone formation in some women receiving estrogens
How do estrogens affect the physiology of the cervix & myometrium?
-
Increase amt of cervical mucus & water content
- Facilitates sperm penetration of the cervix
- Promotes endometrial proliferation
- Increases tubal contractility & favors rhythmic contractions of the uterine myometrium
How and where is progesterone synthesized?
- Progesterone secreted by the ovary
- Corpus luteum (2nd half of menstrual cycle)
- Corticosteroid biosynthesis cascade
What are the two isoforms of the progesterone receptor?
Steroid receptor
PR-A & PR-B
How do PR-A & PR-B differ?
- First 164 N-terminal aa of PR-B are missing from PR-A
- Ratio of isoforms varies on tissue, development, hormones
- PR-B mediates stimulatory actions of progesterone
- PR-A inhibits action of PR-B & a transcriptional inhibitor of other steroid receptors
Progesterone is bound to ______ & _____, but not ______.
Albumin
CBG
SHBG
How is progesterone metabolized?
What is its half life?
- **Rapid first pass metabolism **
- t1/2 = 5 min
- Progesterone –> liver –> hydroxylated metabolites + sulfate/glucuronide conjugates –> eliminated in the urine
What are the physiological effects of progesterone on gonadotropin release?
Decreases frequency of GnRH pulses
Suppression of gonadotropin release
What are the physiological effects of progesterone on the endometrium & the cervix?
-
Decreases estrogen-driven endometrial proliferation
- Development of secretory endometrium
- Changes cervical mucus to scant viscid material
- Importance of maintenance of pregnancy
- Suppresses menstruation & uterine contractility
(Estrogen/Progesterone) is responsible for the increase in basal body tempterature (1°F) mid-menstrual cycle.
Progesterone
Correlates w/ ovulation
How does progesterone impact glucose metabolism?
- Increases basal insulin levels & rise in insulin after carb ingestion
- Minor alteration in glucose tolerance
What are the physiological effects of progesterone on lipid metabolism?
- Progestin & analogs may increase LDL & cause either no effects or modest reductions in serum HDL levels
- 19-norprogestins have more pronounced effects on plasma lipids due to androgenic activity
What are the pharmacological preparations of estrogen? (4)
- 17ß-Estradiol
- Conjugated equine estrogens (Premarin)
- Oral & non-steroidal estrogens
- Ethinyl estradiol
- Mestranol
- Diethylstilbestrol (DES)
What is the application & metabolism of:
- 17ß-Estradiol
- Premarin
- Ethinyl estradiol
- Mestranol
- 17ß-Estradiol
- Oral, patches, creams
- Transdermal route minimizes hepatic effects
- Premarin
- Sulfate esters of estrone, equilin
- **Oral –> esters cleaved in the body **
- Ethinyl estradiol
- Most potent synthetic estrogen (oral)
- C17 ethinyl inhibits 1st pass metabolism
- Mestranol
- **Converted to ethinyl estradiol **
What is the therapeutic use of pharmacologic estrogens? (3)
- Combination oral contraceptives
- Post-menopausal hormone replacement therapy
- Failure of pituitary function/ovarian development
What are some adverse/toxic effects of pharmacologic estrogens?
- Gallbladder disease
- Increased cholesterol levels in bile
- 2-3X increase in gallbladder disease
- Oral estrogens increase risk of thromboembolic disease
- Nausea & vomiting
- Breast swelling
- Migraine headaches
What are the contraindications to pharmacologic estrogens?
- Pregnancy
- Estrogen-dependent cancer
- Undiagnosed abnormal genital bleeding
- History/active thrombophlebitis or thromboembolic disorders
__________ is an anti-estrogen.
**Clomiphene citrate **
What is the composition of Clomiphene citrate?
- Two isomers:
- Zuclomiphene (cis)
- Enclomiphene (trans)
- **Racemic mixture **
What is the mechanism of action of Clomiphene citrate?
**Weak estrogen agonist & potent antagonist **
Partial agonist at estrogen receptors
t1/2 = 5-7 days
What is the therapeutic use of Clomiphene citrate?
- 1st line drug for infertility treatment due to anovulation
- Increases gonadotropin secretion & stimulates ovulation
- Increases amplitude of LH & FSH pulses w/o changing pulse frequency
- Acts on pituitary level to block inhibitory actions of estrogen
- **Causes hypothalamus to release larger amts of GnRH per pulse **
What are the side effects of Clomiphene citrate?
- Ovarian hyperstimulation
- Multiple births
- Hot flashes
- Blurred vision
________ & ________are the selective estrogen receptor modulators (SERMS).
Tamoxifen
Raloxifene
What is the mechanism of action of Tamoxifen?
- Anti-estrogenic, estrogenic, or mixed activity depending on the tissue
- Competitive ER antagonist in breast tissue
- Long t1/2 = 11 days
What is the therapeutic use of Tamoxifen?
- Treatment of breast cancer in women w/ ER + tumors
- Hormonal treatment of choice for early & advanced breast cancer in women of all ages
- Reduces risk of developing contralateral breast cancer
- Primary prevention of breast cancer in women at high risk
What are the adverse effects of Tamoxifen?
- Hot flashes (most common)
- Estrogenic activity in the uterus
- Increases risk of endometrial cancer 2-3X
- Increase in risk of thromboembolic disease
What is the mechanism of action of Raloxifene?
ER agonist in bone
Orally active
t1/2 = 28 hrs
What is the therapeutic use of Raloxifene?
Treatment & prophylaxis of osteoporosis in postmenopausal women & breast cancer
What are the adverse effects of Raloxifene?
- Hot flashes
- DVT
- Leg cramps
- NO endometrial thickening (unlike Tamoxifen)
What are the estrogen synthesis inhibitors? (aromatase inhibitors)
- Type I: Exemestane
- Type II: **Letrozole, Anastrozole **
What is the major therapeutic use & side effects of aromatase inhibitors?
- Treatment of breast cancer
- Dramatically reduced circulating & local levels of estrogens
- Major side effect: hot flashes
What is the mechanism of action of Type I aromatase inhibitors?
- Steroidal (Type I): Exemestane
- Substrate analogs that act as suicide inhibitors
- Irreversibly inactivate aromatase
What is the mechanism of action of Type II aromatase inhibitors?
- Non-steroidal (Type II): Letrozole, Anastrozole
- Interact reversibly w/ heme groups of CYPs
What are the pharmacological preparations of Progestin? (5)
- Progesterone
- Medroxyprogesterone
- Norethindrone
- Norgestrel
- Drospirenone
Administration of:
- Progesterone
- Medroxyprogesterone
-
Progesterone
- Low oral bioavailability
- Micronized, injection, suppositories, gels
-
Medroxyprogesterone
- Injection, oral
- Progesterone analog (ester)
** 19-nortestosterone derivatives**
Mechanism?
Example?
- Testosterone derivatives
- Progestational >> androgenic activity
- Limited binding to glucocorticoid, androgen & mineralocorticoid receptors (accounts for non-progestational activity)
-
Norethindrone
- Orally active
- Ethinyl substituent at C17
- _Slows hepatic metabolism _
What is the composition & mechanism of action of Norgestrel?
- Oral
- Replacement of 13-methyl group of Norethindrone w/ 13-ethyl substituent
- More potent progestin but less androgenic activity
- Racemic mixture of inactive dextrorotatory isomer & active levorotatory isomer, Levonorgestrel
What is the mechanism of action of Drospirenone?
- Spironolactone analogue
- Anti-mineralocorticoid & progestin activity
- K+ should be monitored in women at risk of hyperkalemia
What is the therapeutic use of Drospirenone?
- Pregnancy prevention
- Emotional & physical symptoms of premenstrual dysphoric disorder (reduction of edema)
- Moderate acne vulgaris
What is the therapeutic use of pharmacologic Progestins?
- Hormonal contraception
- Post-menopausal hormone replacement therapy (HRT) [combination w/ estrogen]
- Amenorrhea
- Endometrial hyperplasia
How are progestins used to treat amenorrhea?
- Progestins used for secondary amenorrhea
- Oral (Medroxyprogesterone acetate)
- Given to amenorrheic women for 5-7 days
- Endogenous estrogens stimulate development of a proliferative phase endometrium –> withdrawal bleeding
- Combinations of estrogens & progestins give to test for endometrial responsiveness in patients w/ amenorrhea
How are progestins used to treat endometrial hyperplasia?
Progestins decrease endometrial hyperplasia caused by unopposed estrogen
What are the adverse effects of pharmacologic progestins?
- Breakthrough bleeding
- Headache
- Androgenic effects of 19-nor testosterone derivatives
- Acne
- Hirsutism
What are the progesterone receptor modulators? (2)
Mifepristone (RU-486)
Ulipristal acetate (Ella)
What is the mechanism of action of Mifepristone?
- Competitive receptor antagonist for progesterone receptors
- Some agonist activity
What is the therapeutic use of Mifepristone?
- Combination w/ misoprostol & other prostaglandins
- Termination of early pregnancy (abortifacient)
How does the administration of Mifepristone cause abortion?
- Early stages – decidual breakdown
- **Blastocyst detachment **
- Decrease in hCG production
- Decreases progesterone secretion from the corpus luteum –> accentuates decidual breakdown
- Decreased endogenous progesterone + blockade of progesterone receptors in the uterus
- Increases uterine PG levels
- Sensitizes myometrium to contractile actions
-
Medical abortion
- PG (Misoprostol) given 48 hrs after anti-progestin
- Increase in myometrial contractions
- Ensures expulsion of detached blastocyst
What are the side effects of Mifepristone?
What is the black box warning?
- Vaginal bleeding (8-17 hrs)
- Abdominal pain & uterine cramps
- Nausea, vomiting, diarrhea (PGs)
- Women receiving chronic glucocorticoid therapy should not be given Mifepristone (anti-glucocorticoid activity)
- Black Box Warning: risk of serious, sometimes fatal, infections
What is the mechanism of action of Ulipristal acetate?
Side effects?
- Partial agonist at progesterone receptors
- Blocks progesterone
- Side effects
- Headache
- Abdominal pain
What is the therapeutic use of Ulipristal acetate?
- Emergency contraception
- Blocks ovulation
- Inhibits LH release through interaction w/ the hypothalamus & pituitary
- Inhibits LH-induced follicular rupture in the ovary
- Inhibits ovulation when taken up to 5 days after intercourse
What are the two major uses of estrogens & progesterones?
Hormonal contraception
Postmenopausal hormone replacement therapy
What are the approaches to hormonal contraception w/ regards to estrogen & progesterone?
- Estrogen – progestin combinations
- Progestin only contraceptives
- Post-coital (emergency) contraceptives
- Combined oral contraceptives (ethinyl estradiol-levonorgestrel, 2 doses)
- High dose Levonorgestrel (2 doses)
- Ulipristal (Ella)
What are the therapeutic approaches to postmenopausal hormone replacement therapy?
- Risk vs. benefit approach to therapy
-
Intact uterus
- **Estrogen/progestin combination therapy **
-
Post-hysterectomy
- **Estrogen only **
- Alternatives to estrogen for the treatment of osteoporosis
- Raloxifene (Evista)
- Alendronate (bisphosphonate)
