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33 Cards in this Set

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What is a selective estrogen receptor modulator (SERM)?
Drug which acts as an estrogen agonist in some tissues and as an estrogen antagonist in other tissues.
Name the SERMs.
Clomiphene

Tamoxifen

Raloxifene
What is clomiphene and its therapeutic use?
An orally-active nonsteroidal compound

Used to induce ovulation in females w/ amenorrhea or anovulatory cycles
-- about 80% will ovulate
-- 30-40% will become pregnant

May cause multiple births, stillbirths and ovarian enlargement
Clomiphene MOA?
1. Blockade of estrogen receptor in the hypothalamus interrupts the normal feedback inhibition of GnRH and gonadotropin secretion

2. Blockade of CNS estrogen receptors enhances GnRH secretion which in turn increases FSH and LH secretion

3. Increased FSH and LH stimulate the gametogenesis and estrogen, and multiple ovulation can occur
Clomiphene S/E’s?
Ovarian enlargement

Temporary scintillating scotoma (blurred spots or flashes

Symptoms of menopause (hot flashes, etc.)
Clomiphene contraindications?
Patients w/ thromboembolic disorders
-- acts as a receptor agonist in the liver
-- increases synthesis of clotting factors
Tamoxifen and its therapeutic use?
An orally-active nonsteroidal competitive estrogen receptor antagonist that may have partial agonist properties in some patients.

Used as prophylactic treatment of women at high risk for breast cancer to decrease the incidence of breast cancer.
Tamoxifen MOA?
Blocks estrogen receptors in breast tissue
-- used to treat breast cancer
-- about 75% of breast cancers are estrogen-receptor positive in postmenopausal women
-- not all studies show relationship btwn presence of estrogen receptors in the breastcancer and a positive clinical response to tamoxifen
Other effects of tamoxifen?
1. In postmenpausal women, has the same agonistic (beneficial) effects on bone density and plasma lipid profile as does estrogen

2. Acts as estrogen receptor agonist in LIVER and UTERUS
-- may predispose to venous thrombosis or PE in high risk patients
-- women taking for long periods of time develop endometrial hyperplasia which may predispose to the development of endometrial cancer
Tamoxifen S/Es?
MOST FREQUENT
-- nausea and vomiting resulting from agonistic effects
-- hot flashes resulting from blockade of estrogen receptors
-- same effects as menopause

LESS FREQUENT
-- vaginal bleeding
-- menstrual irregularities

Competitively prevents metabolism of warfarin and may cause PT to increase in patients being treated w/ warfarin
Tamoxifen in PREmenopausal women?
Blocks estrogen receptors in the hypothalamus and pituitary

GnRH↑ --> ↑LH --> ↑[estrogen] which antagonizes the estrogen receptor blockade caused by tamoxifen

This reactive ↑ in [estrogen] can be prevented by tx w/ a GnRH analog
Tamoxifen in POSTmenopausal women?
Acts as an antagonist at estrogen receptors in the hypothalamus and pituitary, but it makes little difference b/c the ovaries have quit making estrogen!
Raloxifene MOA?
Exerts agonistic effects like estrogen on:
-- bone resorption
-- plasma lipid profile
-- hepatic protein synthesis

Acts as an estrogen receptor antagonist in the uterus and breast, so therapy is NOT associated with:
-- breast tenderness
-- increased risk of breast cancer
-- endometrial hyperplasia
-- vaginal bleeding
Raloxifene therapeutic use?
1. decreases size of uterine leiomyomas in postmenopausal women

2. maintains bone density in post-menopausal women b/c it decreases bone resorption by osteoclasts

3. decreases incidence of vertebral fractures by 30-40%, but less effective than HRT by conjugated estrogens

4. appears to decrease the incidence of breast cancer in females at high risk
-- 50% decrease in invasive and non-invasive breast cancer

5. Therapy lowers both Tc and LDL cholesterol, but does not increase HDL cholesterol as does HRT with estrogen
Raloxifene adverse effects?
Hot flashes
Flu-like syndrome
Arthralgia
Thromboembolism (hepatic effect to increase the synth of clotting factors)
Raloxifene interactions?
Oral administration can PREVENT the beneficial effect of the topical application of estradiol in postmenopausal women w/ atropic vaginitis
-- lack of estrogen causes vaginal itching and dryness
How else can postmenopausal bone loss be prevented?
p.o. therapy with bisphophonates which act by inhibiting bone resorption

ALENDRONATE
IBANDRONATE
Bisphosphonate MOA?
Bind avidly to bone surfaces which are remodeling and prevent the bone resorption caused by osteoclasts
Bisphosphonate side effects?
MAJOR
-- esophagitis occurs when patients do not follow the dosing directions
-- should take the drug w/ a glass of water and remains upright for 30 minutes
-- patient should not lie down after the first meal of the day
What is aromatase and why is it important?
Aromatase is a CYP450 enzyme which converts androgens to estrogens
-- testosterone --> estradiol and DHEA --> estrone

It is called aromatase because it converts one of the aliphatic rings in the androgen precursor to a benzene ring (aromatic structure)

In premenopausal women, LH stimulates androstenedione synthesis in thecal cells
-- androstenedione diffuses in to the granulosa cells where it is coverted to testosterone
-- aromatase in the granulosa cells converts testosterone to the potent estrogen estradiol

In postmenopausal women, aromatase located in fat cells converts DHEA made in the adrenal gland to the less potent estrogen estrone
(NB: the adrenal gland can make DHEA, but it cannot make testosterone)

The new aromatase inhibitors do not block CYP450 enzymes which are important in the synthesis of glucocorticoids and mineralocorticoids
What are the aromatase inhibitors?
Anastrozole

Letrozole
Therapeutic uses of aromatase inhibitors?
Treatment of breast cancer in postmenopausal women:
1. with estrogen receptor positive cancer
2. with advanced or metastatic breast cancer
3. who have not responded to tamoxifen
4. who have been taking tamoxifen for five years (switch over after 5 yrs)
Aromatase inhibitor toxicity?
Menopausal symptoms + musculoskeletal problems
What are the progestins?
Micronized progesterone

DERIVATIVES OF 19-NORTESTOSTERONE (which possess some androgenic effects):
1. norethindrone
2. levonorgestrel

PROGESTINS NOT DERIVED FROM 19-NORTESTOSTERONE
1. norgestimate
2. norelgestromin (does not stimulate androgen receptors and therefore does not antagonize the positive effect of estrogen on plasma HDL concentration
3. medroxyprogesterone
OCPs all contain…?
Ethinyl estradiol PLUS…

MONOPHASIC
-- norethindrone
-- levonorgestrel

BIPHASIC
-- norethindrone

TRIPHASIC
-- norethindrone
-- levonorgestrel
-- norgestimate
The Ortho Evra patch…?
Effective in contraception

Single patch delivers 20mcg/day of ETHINYL ESTRADIOL and 150mcg/day or NORELGESTROMIN for up to ten days

Three consecutive weeks of 7-day patches are followed by one patch-free week

Compliance is better compared to daily p.o. OCPs
NuvaRing…?
Vaginal ring used to prevent pregnancy

Ring placed in vagina and removed after three weeks. After one week without a ring, during which menses will occur, a new ring is inserted.

Ring releases 0.015mg/day of ETHINYL ESTRADIOL (EE) and 0.120mg/day of ETONOGESTREL

Total amount of estrogen found in the blood is significantly less than that seen with a transdermal EE patch or combined OCP containing EE

NuvaRing has been reported to cause minimal changes in hemostasis
Contraceptive uses of estrogens/progestins?
Oral contraceptive pills (OCPs)

1. ETHINYL ESTRADIOL is combined w/ the synthetic progestins

2. NORETHINDRONE has low androgenic activity, but norgestrel and desogestrel may cause acne by increasing production of sebum. This androgenic effect can be blocked by treatment with spironolactone.

3. The progestins NORGESTIMATE (used in Ortho-Cyclen and OrthoTriCyclen) and NORELGESTROMIN do not have androgenic effects and do not cause acne

4. The i.m. injection of a depot of 150mg of MEDROXYPROGESTERONE
-- provides contraception lasting three months by causing complete amenorrhea
-- out of 1216 females, two pregnancies occurred, probably as a result of using a smaller dose
-- no increased risk of thromboembolic disease, but unpredictable menstrual bleeding may occur
Acne uses of estrogens/progestins?
In female patients w/ acne, estrogens have a beneficial effect because they act in two ways to decrease plasma free testosterone concentration
1. estrogen acts in the hypothalamus and pituitary to suppress the release of LH; this action decreases testosterone production by the ovaries
2. increased hepatic synth of SHBG decreases plasma free testosterone concentration
3. decreased free testosterone decreases sebum production in the skin

Ortho-Tri-Cyclen containing ETHINYL ESTRADIOL and NORGESTIMATE has been approved for the treatment of moderate acne in females 15 years or older
HRT use of estrogens/progestins?
OCPs are used for HRT

Two methods
1. constant estrogen w/ cyclic or intermittent progestin
2. constant estrogen and progestin
What is the progesterone receptor antagonist?
Mifepristone
Use of mifepristone?
RU-486

1. Outpatient abortion of a fetus less than 49 days old
-- given to interrupt pregnancy followed two days later by the synthetic prostaglandin dinoprostone which contracts uterine smooth muscle
Mifepristone has also been shown to…?
1. prevent implantation of a fertilized egg

2. alleviate the symptoms of endometriosis

3. treat non-resectable meningiomas

4. treat uterine leuimyomas

5. treat patients with Cushing’s syndrome (mifepristone is also a glucocorticoid receptor antagonist)