Week 4: Reproductive pharmacology: Estrogens and Progestins Flashcards

Question

Specific estrogen toxicities when used as HRT

Answer 1

* Estrogen increases the risk of endometrial cancer * this effect is prevented by combining estrogen with a progestin

Answer 2

By combining the estrogen with a progestin

Answer 3

* nausea * breast tenderness * increased risk of migraine headache * thromboembolic events (eg deep vein thrombosis (DVT)) * Gallbladder disease * Hypertriglyceridemia * hypertension

Answer 4

Full antagonists * Fulvestrant Selective-estrogen receptor antagonists * Tamoxifen

Answer 5

Anastrozole

Answer 6

* GnRH agonists * Danazol

Answer 7

A pure full estrogen receptor antagonist (in all tissues)

Answer 8

used in the treatment of women with breast cancer that have developed resistance to tamoxifen

Answer 9

Selective Estrogen Receptor Modulators (SERMs)

Answer 10

* SERMs are mixed estrogen agonists that have estrogen agonist effects in some tissues and act as partial agonists or antagonists of estrogen in other tissues * Interactions of the estrogen receptor with various coregulators appear to be responsible for some of the tissue-specific effects of SERMs

Answer 11

a Selective Estrogen Receptor Modulator (SERM) has mixed agonist and antagnoist effects in various tissues

Answer 12

* effective in the treatment of hormone-responsive breast cancer where it acts as an antagonist * Prophylactic treatment of tamoxifen reduces the incidence of breast cancer in women who are at very high risk * Has greater agonist effect in bone and thus prevents osteoporosis in postmenopausal women

Answer 13

* Works as an agonist on endometrial receptors and thus promotes endometrial hyperplasia and increases the risk of endometrial cancer (**agonist effect**) * Causes hot flushes (**antagonist effect**) * increases the risk of venous thrombosis (**agonist effect**)

Answer 14

A Selective Estrogen Receptor Modulator (SERM) + is a nonsteroidal compound with tissue-specific actions has mixed agonist and antagonist effects on the estrogen receptors of various tissues (tissue-dependent)

Answer 15

* used to induce ovulation in anovulatory women who wish to become pregnant * By selectively blocking estrogen receptors in the pituitary, clomiphene reduces negative-feedback and increases FSH and LH output * This increase in gonadotropins stimulates ovulation

Answer 16

Anastrozole

Answer 17

A non-steroidal competitive aromatase inhibitor

Answer 18

related to anastrozole A non-steroidal competitive aromatase inhibitor

Answer 19

used in the treatment of breast cancer

Answer 20

an **irreversible** aromatase inhibitor **unlike** Anastrozole which is a **competitive** inhibitor

Answer 21

* nonsteroidal **competitive** inhibitors of Aromatase * Aromatase is the enzyme required for the last step in estrogen synthesis * Exemestane is an **irreversible** aromatase inhibitor

Answer 22

Danazol inhibits several cytochrome P450 enzymes involved in gonadal steroid synthesis and is a weak partial agonist of progestin, androgen and glucocorticoid receptors

Answer 23

Sometimes used in the treatment of endometriosis and fibrocystic disease of the breast

Answer 24

The **cotinuous** administration of GnRH agonists (eg Leuprolide) suppresses and thereby inhibits ovarian production of estrogens and progesterone

Answer 25

Leuprolide

Answer 26

\*eg Leuprolide\* GnRH agonists are used in combination with other agents in **controlled** ovarian hyperstimulation and are also used for treatment of precocious puberty in children and short term (\<6 months) treatment of endometriosis and uterine fibroids in women

Answer 27

* Hormonal contraception, either alone or in combination with an estrogen * the presence of progestin reduces estrogen-induced endometrial cancer * Postmenopausal hormone replacement therapy, in combination with Estrogen * Progesterone is used in assisted reproductive technology methods to promote and maintain pregnancy * Long-term ovarian suppression for other purposes

Answer 28

toxicity of progestins is low, but, they may; * increase blood pressure * decrease HDL * Long-term use of high doses in premenopausal women is associated with a reversible decrease in bone density (a secondary effect of ovarian suppression and decreased ovarian production of Estrogen) * delayed resumption of ovulation after termination of therapy

Answer 29

an orally active steroid antagonist of progesterone and glucocorticoids

Answer 30

* Major use is as an abortifacient in early pregnancy (up to 49 days after the last menstrual period) * used with the PGE analog Misoprostol to increase uterine contractions * The combination of Mifepristone and Misoprostol achieves a complete abortion in \>90% of early pregnancies

Answer 31

* The most common complication is failure to induce a complete abortion * Contraindicated during chronic glucocorticoid therapy due to anti-glucocorticoid activity

Answer 32

* Most common complication is failure to induce a complete abortion * Primarily due to misoprostol = NVD * Rarely, patients who use Mifepristone + Misoprostol for medical abortion have experienced serious infection, sepsis and even death due to unusual infection (eg Clostridium sordelli) * Contraindicated during chronic glucocorticoid therapy due to anti-glucocorticoid therapy due to synergystic anti-glucocorticoid activity

Answer 33

* Contraindicated during chronic glucocorticoid therapy due to anti-glucocorticoid therapy due to synergystic anti-glucocorticoid activity * Rarely, patients who use Mifepristone + Misoprostol for medical abortion have experienced serious infection, sepsis and even death due to unusual infection (eg Clostridium sordelli)

Answer 34

* Causes decidual breakdown, blastocyst detachment and decreased hCG production * Decreased hCG results in decreased progesterone secretion from the corpus luteum, causing futher decidual breakdown * Decreased progesterone production and receptor blockade leads to increased prostaglandin levels * causes * myometrial contractions * Cervical softening

Answer 35

two types of preparations * Estrogen + Progestin combination * continuous progestin **w/o** co-administration of an estrogen

Answer 36

**Primary** * Prevent ovulation by suppressing LH and FSH secretion by the anterior pituitary: \*Negative feedback\* * Estrogen acts directly on the anterior pituitary on the anterior pituitary to decrease FSH and LH secretion * Progestins act on the hypothalamus to decrease GnRH release, which reduces FSH and LH secretion by the anterior pituitary **Secondary** * Progesterone thickens cervical mucus, acting as a barrier to sperm * Reduction in endometrial growth interferes with implantation * Slowed uterine tubal motility and ova transport reduce fertilization

Answer 37

* Estrogen acts directly on the anterior pituitary on the anterior pituitary to decrease FSH and LH secretion * Progestins act on the hypothalamus to decrease GnRH release, which reduces FSH and LH secretion by the anterior pituitary Progesterone also thickens the cervical mucus to act as a sperm barrier and also inhibits the endometrium growth and slowed tubal motility resulting in reduced implantation and fertilization respectively but in the wrong order fertiliization would occur first

Answer 38

* Monophasic * Biphasic * Triphasic These attempt to lower total steroid dose and mimic the menstrual cycle 21 vs 28 day packs (inert pills during withdrawal bleed) Estrogen: Ethinyl estradiol 20-35 ug Progestin dose varies due to differences in potency "perfect use" has an effectiveness of 99%

Answer 39

"perfect use" effectiveness is 99%

Answer 40

* Incidence of serious adverse effects associated w/ COCs is lower than the incidence of complications associated with pregnancy Major adverse effects * VTE (3-4 fold ↑ compared to those not taking OCs) * HTN * Lipid effects (↑TG, ↑ cholesterol, ↑ or no change HDL, ↓ LDL) * MI * CV risks are greatest in smoker \> 35 years old Minor-to-moderate side effects * nausea * edema * HA * worsening migraines * breakthrough bleeding * increased skin pigmentation * ↑ skin pigmentation * increased incidence of vaginal infections * amenorrhea

Answer 41

* 50% ↓ in endometrial cancer risk, benefit lasting 15 years after the COCs are stopped * ↓ risk of ovarian cancer * ↓ ovarian cysts and fibrocystic disease * ↓ iron-deficiency anemia * ↓ dysmenorrhea and endometriosis side effects * ↓ ectopic pregnancies and pelvic inflammatory disease

Answer 42

* Estrogens suppress lactation * low dose OCs produce minimal effects on milk production, Low concentrations of OCs are found in breast milk * existing low-quality evidence suggests that combined oral contraceptives may reduce the volume of breastmilk but not affect the growth of infants

Answer 43

* Antibiotics may alter enterohepatic cycling of oral contraceptive metabolites * Multiple pharmacokinetic interactions CYP- and uridine 5'-diphosphate glucuronosyltransferase (UGT) catalyzed reactions * Ethinyl estradiol is metabolized by CYP3A4 and CYP2C9 * UGT1A1 is the predominant UGT for Ethinyl Estradiol * Most progestogens are substrated for CYP3A4 and some metabolites require glucuronidation

Answer 44

often called "minipill"

Answer 45

* GnRH suppression through negative feedback on the hypothalamus is the major mechanism * increases the viscosity of cervical mucus, acting as a physical barrier to sperm penetration * Rapid first-pass metabolism * Same dose taken daily (no inert pills)

Answer 46

"perfect use" effectiveness for Progestin-only OCs is less than COCs

Answer 47

* Breakthrough bleeding is the most common adverse effect (up to 25% of patients) * No evidence of increased VTE * May cause more acne

Answer 48

Ortho Evra patch

Answer 49

* Ortho Evra patch * Combination estrogen and progestin * Ethinyl estradiol and norelgestromin * apply to buttock, abdomen, upper arm or torso * Changed weekly x3 weeks, then 1 week off for withdrawal bleed

Answer 50

* some sensitivites to adhesive have been reported * concerns for higher estrogen levels due to no first-pass effect, ↑ risk of VTE

Answer 51

Combination of estrogen and progestin * Ethinyl estradiol and etonogestrel * 3 weeks in place followed by 1 week off for withdrawal bleed * transmucosal absorption

Answer 52

* issues with expulsion during sexual intercourse * safety profile appears to be the same as with other combined hormonal contraceptives

Answer 53

Etonogestrel (Nexplanon)

Answer 54

Progesterone-only * Etonogestrel is a progestin * Lasts 3 years

Answer 55

possible side effects * HA * weight gain * mood changes * acne * local infection * difficult removal Irregular vaginal bleeding is the norm and pattern is unpredictable Use with caution in those w/ history or predisposition to VTE

Answer 56

Medroxyprogesterone acetate (Depo-Provera)

Answer 57

* Medroxyprogesterone acetate (Depo-Provera) * Given IM * Lasts 12 weeks

Answer 58

* Causes irregular vaginal bleeding and eventual amenorrhea Other possible side effects * HA * Mood changes * Weight gain * ↓ HDL * ↑LDL * ↓ bone density * return to fertility can be delayed Contraindicated in those w/ history or predispotion to VTE

Answer 59

Contraindicated in those w/ history or predisposition to VTE

Answer 60

Levonorgestrel (Mirena)

Answer 61

* Levonorgestrel (Mirena) * 5 year effectiveness * Local progestin concentration ~1000x higher than systemic levels * Thickening of cervical mucus to prevent sperm penetration * Inhibits ovulation in some cases * Reduced endometrial growth * expect spotting for up to 3 months, then light and irregular menses or amenorrhea

Answer 62

Refers to the use of any drug or device to prevent pregnancy after unprotected intercourse or when contraception has failed

Answer 63

Levonorgestrel as Plan B or Plan B one-step

Answer 64

Levonorgestrel plan B * Most effective within 72 hours of unprotected sex * prevention of ovulation, blocking implantation, increased cervical mucus viscosity * available without prescription

Answer 65

* 30 mg single dose * inhibits ovulation via inhibition of LH release * May block implantation of fertilized egg (uncertain) * Effective up to 120 hours after unprotected sex * Available by perscription only * May be more efficacious than levonorgestrel for overweight (BMI \>25 kg/m2) women

Answer 66

self-limited HA and abdominal pain

Answer 67

Ulipristal acetate (Ella)

Answer 68

reasonably efficacious and safe

Answer 69

* Less effective * More NV * Theoretical concerns of VTE

Answer 70

Copper IUD (Paragard) * Most effective: 1% failure rate when inserted up to 5 days after unprotected sex * Provides 10 years of contraception * Copper is toxic to sperm * Copper increases inflammation in the uterus, which reduces sperm viability and reduces endometrial receptivity

Answer 71

* Clomiphene citrate * Gonadotropins * Human chorionic gonadotropin * Progesterone replacement in progesterone deficient women * Insulin sensitizers (metformin)

Answer 72

Ovulation induction for infertility

Answer 73

* Estrogen antagonist, blocking inhibitory effect on gonadotropin release from pituitary * Increases gonadotropin secretion (FSH\>LH), stimulating ovulation

Answer 74

* Ovarian hyperstimulation * multiple gestation * ovarian cysts * HA * hot flushes * blurry vision * luteal phase defect due to inadequate progesterone production * increased ovarian cancer risk with prolonged use

Answer 75

* Methotrexate

Answer 76

* as antimetabolite: folic acid antagonist * Disrupts rapidly proliferating trophoblast * Used to treat certain types of cancer (for example gestational trophoblastic disease - choriocarcinoma) Psoriasis, RA * Can be used to terminate an intrauterine pregnancy, followed by misoprostol to induce uterine contractions, but mostly replaced by mifepristone now

Answer 77

* as antimetabolite: Folic acid antagonist * Used in medical management of ectopic pregnancy \< 3.5 cm, no cardiac activity, hemodynamically stable, can adhere to f/u * Management is generally outpatient with frequent follow-up of labs and physical exam * Used to treat certain types of cancer (for example gestational trophoblastic disease = choriocarcinoma), psoriasis, RA

Answer 78

* Liver damage * lung damage * damage to the lining of the mouth, stomach or intestines * Increased risk of lymphoma * serious or life-threatening skin reactions * immunosuppression

Week 4: Reproductive pharmacology: Estrogens and Progestins Flashcards

(126 cards)