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Reproductive System > Female Reproductive Pharmacology > Flashcards

Female Reproductive Pharmacology Flashcards

1
Q

What are the 3 major estrogens?

A

Estradiol-17ß

Estrone

Estriol

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2
Q

_______ is the most potent estrogen.

_______ exists in equilibrium w/ estradiol.

_______ has minimal estrogenic activity.

A

Estradiol-17ß

Estrone

Estriol

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3
Q

Estrogens are normally bound to _____ & ______.

A

SSBG

**Albumin **

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4
Q

Estradiol undergoes what kind of biotransformation?

Estrogens undergo ________ recirculation.

A
  • Hepatic biotransformation
    • Estradiol –> Estrone –> Estriol
    • Estriol = major urinary metabolite
  • Enterohepatic circulation
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5
Q

What are the 2 types of nuclear estrogen receptors?

How are they activated?

What is their mechanism of action?

A
  • ER-α & ER-ß
  • Ligand-activated transcription factors
  • Increase/decrease transcription of target genes
  • Multiple mRNA isoforms (promoters & alternative splicing)
  • Ligand mediated ER conformation
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6
Q

What are the physiological effects of estrogen on the skeletal system?

A
  • Enhances skeletal maturation & epiphyseal growth plate closure to limit linear growth
    • effects on bone mass
      • Decrease # & activity of osteoclasts
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7
Q

Estrogen is responsible for feedback regulation of ___________ release.

A

Gonadotropin

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8
Q

What are the physiological effects of estrogen on lipid metabolism?

A
  • Slightly elevates serum TGs & slightly reduces total serum cholesterol levels
  • Increase HDL
  • Decrease LDL & LPA
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9
Q

How does estrogen affect the clotting cascade?

A
  • 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
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10
Q

How does estrogen affect cholesterol & bile acid secretion?

A
  • Increase cholesterol secretion
  • Decrease bile acid secretion
  • Increased saturation of bile w/ cholesterol
  • Basis for increased gallstone formation in some women receiving estrogens
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11
Q

How do estrogens affect the physiology of the cervix & myometrium?

A
  • 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
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12
Q

How and where is progesterone synthesized?

A
  • Progesterone secreted by the ovary
  • Corpus luteum (2nd half of menstrual cycle)
  • Corticosteroid biosynthesis cascade
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13
Q

What are the two isoforms of the progesterone receptor?

A

Steroid receptor

PR-A & PR-B

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14
Q

How do PR-A & PR-B differ?

A
  • 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
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15
Q

Progesterone is bound to ______ & _____, but not ______.

A

Albumin

CBG

SHBG

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16
Q

How is progesterone metabolized?

What is its half life?

A
  • **Rapid first pass metabolism **
  • t1/2 = 5 min
  • Progesterone –> liver –> hydroxylated metabolites + sulfate/glucuronide conjugates –> eliminated in the urine
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17
Q

What are the physiological effects of progesterone on gonadotropin release?

A

Decreases frequency of GnRH pulses

Suppression of gonadotropin release

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18
Q

What are the physiological effects of progesterone on the endometrium & the cervix?

A
  • 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
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19
Q

(Estrogen/Progesterone) is responsible for the increase in basal body tempterature (1°F) mid-menstrual cycle.

A

Progesterone

Correlates w/ ovulation

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20
Q

How does progesterone impact glucose metabolism?

A
  • Increases basal insulin levels & rise in insulin after carb ingestion
  • Minor alteration in glucose tolerance
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21
Q

What are the physiological effects of progesterone on lipid metabolism?

A
  • 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
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22
Q

What are the pharmacological preparations of estrogen? (4)

A
  • 17ß-Estradiol
  • Conjugated equine estrogens (Premarin)
  • Oral & non-steroidal estrogens
    • Ethinyl estradiol
    • Mestranol
    • Diethylstilbestrol (DES)
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23
Q

What is the application & metabolism of:

  • 17ß-Estradiol
  • Premarin
  • Ethinyl estradiol
  • Mestranol
A
  • 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 **
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24
Q

What is the therapeutic use of pharmacologic estrogens? (3)

A
  • Combination oral contraceptives
  • Post-menopausal hormone replacement therapy
  • Failure of pituitary function/ovarian development
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25
Q

What are some adverse/toxic effects of pharmacologic estrogens?

A
  • 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
26
Q

What are the contraindications to pharmacologic estrogens?

A
  • Pregnancy
  • Estrogen-dependent cancer
  • Undiagnosed abnormal genital bleeding
  • History/active thrombophlebitis or thromboembolic disorders
27
Q

__________ is an anti-estrogen.

A

**Clomiphene citrate **

28
Q

What is the composition of Clomiphene citrate?

A
  • Two isomers:
    • Zuclomiphene (cis)
    • Enclomiphene (trans)
  • **Racemic mixture **
29
Q

What is the mechanism of action of Clomiphene citrate?

A

**Weak estrogen agonist & potent antagonist **

Partial agonist at estrogen receptors

t1/2 = 5-7 days

30
Q

What is the therapeutic use of Clomiphene citrate?

A
  • 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 **
31
Q

What are the side effects of Clomiphene citrate?

A
  • Ovarian hyperstimulation
  • Multiple births
  • Hot flashes
  • Blurred vision
32
Q

________ & ________are the selective estrogen receptor modulators (SERMS).

A

Tamoxifen

Raloxifene

33
Q

What is the mechanism of action of Tamoxifen?

A
  • Anti-estrogenic, estrogenic, or mixed activity depending on the tissue
  • Competitive ER antagonist in breast tissue
  • Long t1/2 = 11 days
34
Q

What is the therapeutic use of Tamoxifen?

A
  • 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
35
Q

What are the adverse effects of Tamoxifen?

A
  • Hot flashes (most common)
  • Estrogenic activity in the uterus
  • Increases risk of endometrial cancer 2-3X
  • Increase in risk of thromboembolic disease
36
Q

What is the mechanism of action of Raloxifene?

A

ER agonist in bone
Orally active

t1/2 = 28 hrs

37
Q

What is the therapeutic use of Raloxifene?

A

Treatment & prophylaxis of osteoporosis in postmenopausal women & breast cancer

38
Q

What are the adverse effects of Raloxifene?

A
  • Hot flashes
  • DVT
  • Leg cramps
  • NO endometrial thickening (unlike Tamoxifen)
39
Q

What are the estrogen synthesis inhibitors? (aromatase inhibitors)

A
  • Type I: Exemestane
  • Type II: **Letrozole, Anastrozole **
40
Q

What is the major therapeutic use & side effects of aromatase inhibitors?

A
  • Treatment of breast cancer
  • Dramatically reduced circulating & local levels of estrogens
  • Major side effect: hot flashes
41
Q

What is the mechanism of action of Type I aromatase inhibitors?

A
  • Steroidal (Type I): Exemestane
  • Substrate analogs that act as suicide inhibitors
  • Irreversibly inactivate aromatase
42
Q

What is the mechanism of action of Type II aromatase inhibitors?

A
  • Non-steroidal (Type II): Letrozole, Anastrozole
  • Interact reversibly w/ heme groups of CYPs
43
Q

What are the pharmacological preparations of Progestin? (5)

A
  • Progesterone
  • Medroxyprogesterone
  • Norethindrone
  • Norgestrel
  • Drospirenone
44
Q

Administration of:

  • Progesterone
  • Medroxyprogesterone
A
  • Progesterone
    • Low oral bioavailability
    • Micronized, injection, suppositories, gels
  • Medroxyprogesterone
    • Injection, oral
    • Progesterone analog (ester)
45
Q

** 19-nortestosterone derivatives**

Mechanism?

Example?

A
  • 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 _
46
Q

What is the composition & mechanism of action of Norgestrel?

A
  • 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
47
Q

What is the mechanism of action of Drospirenone?

A
  • Spironolactone analogue
  • Anti-mineralocorticoid & progestin activity
  • K+ should be monitored in women at risk of hyperkalemia
48
Q

What is the therapeutic use of Drospirenone?

A
  • Pregnancy prevention
  • Emotional & physical symptoms of premenstrual dysphoric disorder (reduction of edema)
  • Moderate acne vulgaris
49
Q

What is the therapeutic use of pharmacologic Progestins?

A
  • Hormonal contraception
  • Post-menopausal hormone replacement therapy (HRT) [combination w/ estrogen]
  • Amenorrhea
  • Endometrial hyperplasia
50
Q

How are progestins used to treat amenorrhea?

A
  • 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
51
Q

How are progestins used to treat endometrial hyperplasia?

A

Progestins decrease endometrial hyperplasia caused by unopposed estrogen

52
Q

What are the adverse effects of pharmacologic progestins?

A
  • Breakthrough bleeding
  • Headache
  • Androgenic effects of 19-nor testosterone derivatives
    • Acne
    • Hirsutism
53
Q

What are the progesterone receptor modulators? (2)

A

Mifepristone (RU-486)

Ulipristal acetate (Ella)

54
Q

What is the mechanism of action of Mifepristone?

A
  • Competitive receptor antagonist for progesterone receptors
  • Some agonist activity
55
Q

What is the therapeutic use of Mifepristone?

A
  • Combination w/ misoprostol & other prostaglandins
  • Termination of early pregnancy (abortifacient)
56
Q

How does the administration of Mifepristone cause abortion?

A
  • 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
57
Q

What are the side effects of Mifepristone?

What is the black box warning?

A
  • 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
58
Q

What is the mechanism of action of Ulipristal acetate?

Side effects?

A
  • Partial agonist at progesterone receptors
  • Blocks progesterone
  • Side effects
    • Headache
    • Abdominal pain
59
Q

What is the therapeutic use of Ulipristal acetate?

A
  • 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
60
Q

What are the two major uses of estrogens & progesterones?

A

Hormonal contraception

Postmenopausal hormone replacement therapy

61
Q

What are the approaches to hormonal contraception w/ regards to estrogen & progesterone?

A
  • 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)
62
Q

What are the therapeutic approaches to postmenopausal hormone replacement therapy?

A
  • 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)

Reproductive System (35 decks)

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