Walters-Estrogens

Front 1

How does estrogen therapy prevent osteoporosis?

Back 1

1) ↓ synthesis by osteoblasts of osteoclast-stimulating cytokines (IL-1, IL-6, TNFα)
2) ↑ synthesis by osteoblasts of anti-resorptive factors (IGF-1, transforming growth factor-β (TGF-β), bone morphogenic protein-6 (BMP-6)
3) ↑ synthesis osteoprotegerin by osteoblasts -> apoptosis of osteoclasts

Front 2

How does estrogen therapy prevent vasomotor symptoms (hot flashes)?

Back 2

Estrogens ↑ synthesis and release of 5-HT & β-endorphins-> decrease NE in preoptic hypothalamus -> increase threshold for activation of cooling mechanisms (to normal levels)

Front 3

How is estrogen used as an oral contracepive?

Back 3

inhibit ovulation
MECHANISM: (-) feedback inhibition of LH/FSH
(Generally given with a progestin)

Front 4

list the therapeutic uses of estrogen

Back 4

1. MENOPAUSAL HORMONE THERAPY (MHT)
a. osteoporosis
b. vasomotor symptoms (hot flashes
c. UROGENITAL ATROPHY – dryness, itching, pain on urination
2. oral contraception
3. dysmenorrhea (NSAIDs also used)
4. prostate and breast cancer

Front 5

list the side effects of estrogen

Back 5

1. FLUID RETENTION & ↑ BP: MOA-increased transcription of angiotensinogen
2. ↑ TRIGLYCERIDES
3. ↑ THROMBOEMBOLIC DISORDERS (DVT)-from ↑ clotting factors & decreased antithrombin III
4. ↑ GALLBLADDER DISEASE-Bile cholesterol levels are ↑
5. E2-↑ risk of “probable” dementia
6. ENDOMETRIAL CANCER (endometrial hyperplasia)-15x ↑ incidence when unopposed by progestin
7. BREAST CANCER- ↑ Risk in postmenopausal ♀; E2 alone does not induce breast cancer but can promote if preexisting cancer
8. LIVER CANCER – ↑↑ risk w/ E2 + progestin (Tumors are larger & more irregular)
9. ↑ RISK CERVICAL CANCER
10. ↑ RISK OVARIAN & LUNG CANCER in postmenopausal women

Front 6

Describe how estrogen therapy can lead to cancer

Back 6

1. trophic effects of estrogens
2. certain tissues prone to cancer (uterus, breast, ovary, prostate) contain CYP1B1 that metabolize 4-hydroxy-catechol estrogens to semiquinones or quinones and generate reactive O2 species that damage DNA

Front 7

list the SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMS) and describe the class side effects

Back 7

1. tamoxifen
2. toremifene
3. raloxifene
SIDE EFFECTS: hot flashes, vaginal discharge, nausea, increased risk of DVT & PE

Front 8

describe tamoxifen

Back 8

AGONIST:
bone-inhibits resorption
liver- ↓s total & LDLc
endometrium-stimulates proliferation
ANTAGONIST:
tumor cells-inhibits synthesis of TGF-β which regulates cell proliferation & differentiation
ANTAGONIST MECHANISM: activation of histone deacetylase-->inhibit transcription
USE: prevent & tx ER+ breast cancer

Front 9

describe toremifene

Back 9

analog of tamoxifen for breast cancer in postmenopausal ♀

Front 10

describe raloxifene

Back 10

Agonist effects:
a) Inhibits bone resorption
b) decreases total & LDLc
Antagonist effects: Antiproliferative in uterus and breast (can use for combined effects of reducing uterine and breast cancers and treat osteoporosis)
USE: Prevent & tx osteoporosis in postmenopausal women

Front 11

describe fulvestrant

Back 11

SELECTIVE ESTROGEN RECEPTOR DOWNREGULATOR (SERD)
MOA-inhibits binding of E2 by altering receptor structure--> internalization of ER
USE: ER+ breast cancer that has progressed despite treatment with tamoxifen

Front 12

list the ovulation stimulants and describe the class side effects

Back 12

1. clomiphene
2. menotropins
3. urofollitropin
4. FOLLITROPIN ALPHA
5. FOLLITROPIN ALPHA/BETA
6. LEUTROPIN ALPHA (Luveris)-used w/ FSH to stimulate follicular development
7. CHORIONIC GONADOTROPIN (hCG)
8. CHORIOGONADOTROPIN ALPHA (recombinant hCG)
Side Effects:
1. multiple births
2. Ovarian hyperstimulation syndrome (OHSS)- ↑ vascular permeability-->accumulation of fluid in peritoneum, thorax and pericardium (life threatening)
Sx: abdominal pain/distention, ovarian enlargement, acute respiratory distress syndrome, thromboembolic events & hepatic dysfunction

Front 13

describe the mechanism of clomiphene

Back 13

blocks E2 receptors-->lose negative feedback inhibition to LH and FSH-->LH and FSH increase

Front 14

describe urofollitropin

Back 14

Purified FSH from urine of postmenopausal women; postmenopausal women have decreased E2-->decreases (-) feedback on FSH-->increases urinary FSH
HOW DOES FSH ALONE INDUCE OVULATION? Relies on HL surge-->release of multiple follicles-->multiple births

Front 15

describe the uses of the hCG drugs

Back 15

1. CHORIONIC GONADOTROPIN-hCG from urine of pregnant women
USES: cryptorchism, hypogonadism, stimulate ovulation; hormone measured in pregnancy test kits
2. CHORIOGONADOTROPIN ALPHA-recombinant hCG
USES-induce follicular maturation & luteinization & stimulate ovulation; tx cryptorchism

Front 16

describe GnRH agonists

Back 16

MECHANISM: downregulate GnRH receptors (initial release (surege) of GnRH; prolonged stimulation causes receptors in anterior pituitary to downregulate)
1. LEUPROLIDE
2. HISTRELIN
3. NAFARELIN
4. TRIPTORELIN
5. GOSERELIN
USES-prostate & breast cancers, precocious puberty, endometriosis, priapism, inhibit LH surge to prevent ovulation
CLASS SIDE EFFECT-potential for hyperglycemia

Front 17

describe GnRH antagonists

Back 17

MOA-inhibit premature surges in LH in women undergoing controlled ovarian hyperstimulation
ADVANTAGE OVER GnRH AGONISTS-Don’t get initial surge
1. CETRORELIX (Cetrotide
2. GANIRELIX (generic)
Side effects: hypersensitivity reactions (anaphylaxis)

Front 18

describe progestins

Back 18

PRIMARY PROGESTIN-progesterone; synthesized in corpus luteum
Promote cell differentiation & development of secretory endometrium; sustain pregnancy by suppressing menstruation & uterine contractility; abrupt ↓ in levels signals onset of menses
MECHANISM-bind progestin receptors that regulate gene transcription
EFFECTS: a) increase metabolism of E2-->E1
b) decreased transcription of E2 receptors
TX USES OF PROGESTINS:
1. Oral contraception
2. Menopausal hormone therapy (MHT)
3. Abnormal uterine bleeding
4. Amenorrhea & dysmenorrhea
5. Metastatic endometrial carcinoma
side effects- ↑ incidence HTN, MI, thrombosis, LDLc

Front 19

list and describe the progestins

Back 19

1. progesterone
2. medroxyprogesterone: long-term contraceptive given IM q 3 months to inhibit release of gonadotropins from anterior pituitary
BBW-long term use significantly decreases bone density
3. MEGESTROL-breast & endometrial cancer; anorexia in AIDS patients
4. NORETHINDRONE-5mg for amenorrhea, abnormal uterine bleeding and endometriosis; most common progestin in oral contraceptives at much lower dose (0.35 mg)
Contraindicated if Hx of breast cancer, DVT or PE

Front 20

describe tranexamic acid

Back 20

anti-fibrinolytic lysine analog competes at lysine binding site on plasminogen preventing activation of plasminogen to plasmin-->preventing degradation of fibrin clots-->blood clots-->decreased bleeding
used for abnormal or heavy menstrual bleeding

Front 21

describe prempro

Back 21

conjugated estrogen + medroxyprogesterone for vasomotor Sx of menopause, vulvar & vaginal atrophy, osteoporosis

Front 22

describe angelique

Back 22

E2 + drospirenone
Drospirenone is mineralocorticoid antagonist; counters Na/H2O retention by E2
side effect-hyperkalemia
Uses: vasomotor Sx of menopause, vulvar & vaginal atrophy, osteoporosis

Front 23

describe how oral contraceptives work

Back 23

Most combine estrogen + progestin; both feed back on anterior pituitary & hypothalamus to ↓ release of gonadotropins
Progestins also inhibit LH surge--> inhibit ovulation

Front 24

describe side effects of oral contraceptives

Back 24

SIDE-EFFECTS-varies w/ ratio of estrogen to progestin
1. High estrogen content can ↑ withdrawal bleeding, mastalgia & edema & can suppress lactation & cause breast enlargement
2. Breakthrough bleeding more common in preparations w/ low estrogen (predominantly progesterone-stimulated endometrium is fragile and bleeds more easily); biphasic & triphasic OCs ↓ breakthrough bleeding
3. Headache, weight gain and acne are progestin-related androgenic effects and can be minimized by choosing product w/ more estrogen and less progestin

Front 25

describe non-oral contraceptives

Back 25

1. ORTHO EVRA-patch applied weekly
FDA BLACK BOX WARNING: sudden release of Rx--> ↑ risk of venous thromboembolism (VTE) and strokes
2. NUVA RING-remains in place 3 wks followed by withdrawal bleeding; alters cervical mucus which impedes sperm & reduces chance of implantation
3. BEYAZ-Folate decreases risk of neural tube defects
uses: OC; premenstrual dysphoric disorder (PMDD); acne vulgaris
4. SAFYRAL-similar to Beyaz

Front 26

describe progestin only oral contraceptives (OCs)

Back 26

Progestins alone don’t always inhibit ovulation but do thicken cervical mucus and alter endometrium which inhibits fertilization and implantation
menstrual cycle is more irregular and there is more breakthrough bleeding
associated with glucose intolerance but not a problem w/ lower dose (CAUTION if diabetic)
Headache, weight gain & acne are more likely w/ progestin only products due to higher doses than found in combination products
PREFERRED FOR-HTN b/c less edema; prior thromboembolism b/c no effect on clotting factors; E2-dependent cancers

Front 27

list non-oral progestin contraceptives

Back 27

1. MICRONOR
2. LEVONORGESTREL-RELEASING INTRAUTERINE SYSTEM (LRIS)-implanted up to 5 yrs in women who have already had at least 1 child and who do not have Hx of ectopic pregnancy or PID\
3. medroxyprogesterone
4. IMPLANON-matchstick size implant of etonogestrel; placed under skin x 3 years

Front 28

describe emergency postcoital contraception

Back 28

intraception or morning after pill; used after unprotected sex or suspicion of contraceptive failure
1. PLAN B-1st tablet w/in 72 hrs of intercourse & 2nd tablet 12 hrs later (80% effective)
2. MIFEPRISTONE-used for postcoital contraception in low doses; higher doses used as abortifacient
3. ULIPRISTAL-selective progesterone receptor modifier (agonist/antagonist) for use w/in 5 days of contraceptive failure or unprotected sex; inhibits or delays ovulation
Side effects-abdominal pain, dysmenorrhea