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153 Cards in this Set
- Front
- Back
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prototype for estrogens
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conjugated estrogens
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prototype for progestins
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medroxyprogesterone acetate
levonorgestrol (Plan B) |
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protoype estrogen R inhibitors
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tamoxifen, raloxiphene
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progesterone receptor inhibitor prototype
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mefepristone (RU486)
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aromatase inhibitor prototype
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anastrozole
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androgen prototype
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stanazolol
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5α-reductase inhibitor prototype
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finasteride
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androgen receptor inhibitor prototype
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flutamide
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what cells is estrogen released from?
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inner granulosa and theca cells in response to FSH/LH
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where is progesterone released from?
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corpus luteum of the mature follicle
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what does estrogen feedback to inhibit?
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FSH (ant. pit)
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what does progesterone feedback to inhibit?
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acts on ant. pit. to inhibit hormonal relase
AND on hypothalamus (inhib GnRH) |
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What's the prototype for estrogens?
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conjugated estrogens (Premarin)
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major estrogen produced by women?
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estradiol
chemically alter this form to increase oral bioavailability of drug form |
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what binds estrogens in the plasma?
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sex hormone binding globulin
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how do estrogens get to their target site?
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bound to sex hormone-binding globulin in plasma
dissociate to enter cell intracellular estrogen receptor |
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estrogen receptor
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intracellular
functions as a tsc factor regulate estrogen response element (ERE) 2 distince genes of ER: α and β these genes belong to Nuclear Hormone Receptor family can fxn w/o estrogen (imp't in cancer) |
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what's the estrogen response element?
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genes w/ a specific DNA sequence that is regulated by the estrogen receptor
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how are conjugated estrogens given?
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usually oral, can be transdermal
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uses of estrogens?
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Premarin:
1. primary hypogonadism (stim 2ardy sex characteristics) 2. use w/ progestin for oral contraceptive 3. relief of menopausal Sx (HRT, ERT) 4. prevent osteoporosis w/ age 5. infertility, partial agonist clomiphene |
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S/E's of estrogens?
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Postmenopausal uterine bleeding, nausea, breast tenderness, hyperpigmentation.
Higher risk of endometrial, ovarian, breast cancer, and stroke. |
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according to WHI study in JAMA 2002, should estrogen be given for primary prevention of CHD?
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No b/c risks of ovarian cancer, etc, outweigh benefit
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medroxyprogesterone acetate (MPA)
levonorgestrol |
prototypes for progestins
synthetic progestins have less androgenic activity |
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endogenous precursor of progesterone?
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pregnenolone
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what's pregnenolone?
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endogenous precursor for progesterone, estrogens, androgens, and adrenocortical steroids
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what's the difference in activity between endogenous and synthetic progestins?
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synthetic have less androgenic activity
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where's the site of action for progesterone?
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intracellular progesterone receptor:
(similar to estrogen R) specific regulatory sites on genes called PRE's that mediate the transcriptional response to progesterone |
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uses of progesterones?
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HRT and contraception both alone or in combo w/ estrogen (COC)
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when is levonoregestrel used by itself?
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a Progesterone:
as Plan B for emergency contraception must be prescribed by a physician not approved OTC |
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S/E's of progesterone?
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same as estrogens:
postmenopausal uterine bleeding, nausea, breast tenderness, hyperpigmentation. Higher risk of endometrial, ovarian, breast cancer, and stroke. |
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what are SERMs
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family of selective estrogen-receptor modulators
includes Tamoxifen: Antagonist in breast but estrogen Agonist in uterus and bone other drugs differ in sites of action and effect |
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why is tamoxifen so useful?
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because it's a selective modulator:
estrogen antagonist in breast estrogen agonist in uterus and bone |
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why is raloxiphene useful?
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efficacious in treatment of breast cancer especially b/c no assoc. w/ developing endometrial cancer (seen in small percent w/ tamoxifen)
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how do estrogen receptor inhibitors work?
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inhibit binding of estrogen to ER which reduces estrogen dependent activity
can be competitive or partial agonists |
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how are estrogen receptor inhibitors and SERMs given?
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orally
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what is tamoxifen the preferred tx for?
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palliative treatment of hormone-dependent metastatic breast cancer in PREmenopausal women.
(Although new studies suggest raloxiphene may be as effective and we are awaiting the results of longterm studies with aromatase inhibitors for women of this age.) |
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can ER inhibitors be given preventatively?
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this is being studied in individuals at high risk for breast cancer
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what are the S/E's of estrogen receptor inhibitors?
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1.Small risk endometrial cancer with tamoxifen no risk with raloxiphene.
2. Increased risk venous thromboembolism |
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mifepristone (RU486)
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prototype progesterone receptor inhibitor
high affinity agonist at BOTH progestin and glucocorticoid receptors |
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site and mechanism of action for progesterone receptor inhibitors?
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exactly like it sounds
(similar mechanism to SERMs) |
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use of progesterone receptor inhibitors?
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1. terminate early pregnancy
2. potential contraceptive 3. potential for tx of tamoxifen resistant breast cancer |
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S/E's of progesterone receptor inhibitors?
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vomiting
diarrhea abd or pelvic pain vaginal bleeding |
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anastrozole (arimidex)
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prototype for aromatase inhibitors
nonsteroidal inhibitor of aromatase |
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what does aromatase do?
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enzyme req'd for synth of estrogens from testosterone and from androsenedione (precursor of estrone and estradiol)
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what's the precursor of estrone and estradiol?
what's the enzyme responsible for the conversion to estrogens? |
androstenidione is converted by the enzyme aromatase to estrone and testosterone
it also converts testosterone to estradiol |
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what's the precursor for pregnenolone?
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cholesterol:
w/o it you can't form progesterone, corticosteroids, testosterone, estrogens, DHEA, etc. |
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what are aromatase inhibitors used for?
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tx of breast cancer resistant to tamoxifen in Premenopausal women
maybe tx of choice for advanced cancers |
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why might aromatase inhibitors be better than SERMs for tx of advanced cancer?
what's the concern? |
no S/E of thrombosis or endometrial cancer
But, some concern for bone loss and possible increase in Heart Dz or impair cognition |
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some potential S/E's of aromatase inhibitors (anastrozole)
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depends on the drug:
bone loss increase heart dz (?) impair cognition (?) |
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what's the prototype for androgen therapy?
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stanozolol
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most important human androgen?
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testosterone
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why can't testosterone be given orally?
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even though it's rapidly absorbed, converted to inactive metabolites
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what's the difference b/w testosterone and synthetic androgens like stanozolol?
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variety fo different analogues w/ both androgenic and anabolic activity after oral administration
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what's the site of action for androgens?
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bind intracellular androgen receptor
recognizes ARE sequence in genome |
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What age should not be given androgens?
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infants
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what are some therapeutic uses for androgens?
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1. androgen RT (men)
2. tx of some gynecologic disorders 3. chemotx for breast tumors in premenopausal women 4. anabolic agent to reverse protein loss after trauma or degenerative conditions 5. infractory anemias 6. osteoporosis 7. stim growth in boys w/ delayed puberty |
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S/E's of androgens?
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1. masculinization in women
2. feminization in men/kids 3. Na+ retention, edema in pts w/ heart, kidney dz 4. increase CV dz b/c of change in lipid profile 5. psychological dependence, aggression, psychosis |
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whats another use off-label use of androgens?
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anabolic steroids in sports
doses 10-200x daily production assoc. w/ sudden death |
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what is finasteride?
what's flutamide? |
5α-reductase inhibitor
androgen receptor inhibitors |
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what are 3 uses of 5α-reductase inhibitors and androgen receptor inhibitors?
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1. hirsutism (women)
2. early male pattern baldness 3. prostatic carcinoma (being studied) |
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what effect does finasteride have on prostate cancer?
what's the drawback? |
it prevents or delays the appearance of prostate cancer
also,decreases urinary problems sexual side effects more common and increased risk high-grade prostate cancer |
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what are different kinds of steroid hormones?
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corticosteroids (gluco/mineralocoriticoids)
Ca+2-regulating steroid H's (Vit D) Gonadal H's (est/progest/androgens |
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How is GnRH released?
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in pulses from the hypothalamus
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what does LH stimulate?
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corpus luteum--estrogen and progesterone production
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what does FSH stimulate?
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graafian follicle
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where does estradiol come from in men?
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testis (from testosterone)
2-25 ug |
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estradiol
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main secretory product of ovary
main estrogen in premenopausal women |
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what's the most potent form of estrogen?
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17-b-estradiol
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what's the main estrogen in men and POSTmenopausal women?
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estrone
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Where is estrone found?
where's it made? |
main estrogen in men and postmenopause
derived from estradiol (1/10th potency) also produced in the liver peripheral aromatization |
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which estrogen is made in non-ovarian tissue?
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estrone made in peripherl tissue by aromatization of adrenal adrostenedione
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where is estriol mainly found?
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main estrogen of urine
also produced in the liver |
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how man carbons do estranes have?
adrostanes? Pregnanes? |
18
19 21 |
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what's the rate limiting step in steroid production?
what enzyme does it depend on? |
production of pregnenolone (C-21) from Cholesterol (C27)
Desmolase is the enzyme that cleaves a 6-C residue (cAMP/PKA) |
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where is desmolase found?
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in mito of steroid-producing cells
pregnenolone then moves to cytoplasm for further processing |
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which ring in the estrogen molecule is crucial for ER binding?
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the Phenolic A ring interacts w/ ER
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what does 5alpha-reductase do?
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converts testosterone to DHT
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why can't natural steroids be administered orally?
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high 1st pass effect
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what binds sex hormones in plasma?
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tightly bound to sex-hormone binding protein (SHBG)
weakly bound to albumin only unbound fraction active <20% |
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are sex hormones active in their circulating form?
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converted Enzymatically to active form in target tissue:
testosterone to DHT via 5a-reductase in prostate or to estradiol by aromatase in brain and liver |
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how can the high 1st pass effect seen w/ sex hormones be prevented?
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non-oral administration:
skin/mucous membrane absorption vaginal (rapid; saline) cream (slower) injection (rapid as crystalline or oil) modified/synthetic form |
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what's the use of HRT?
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1. reinstate sexual maturation: develop 2ary sex charact
2. prevent osteoporosis, etc assoc. w/ menopause or surgically induced changes |
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what are some of the diverse therapeutic potential uses of hormone therapy?
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HRT
contraception infertility breast/prostate cancer |
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failure to produce changes in early puberty:
primary ovarian failure hypogonadism (LH-RH def or hypopit) can be treated how? |
estradiol therapy low dose
higher dose for breast develop and feminization progestins induce cyclic bleeding |
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why is prevention of osteoporosis so important? how can hormones help?
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1.3 million related fractures
12-20% of elderl die due to related complications 12th leading cause of death U.S. HRT has protective effects |
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what are some vasomotor symptoms associated w/ menopause that can be treated w/ HRT?
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hot flashes
inappropriate sweating mood changes vaginitis |
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why is HRT used to decrease risk of CHD?
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increases ratio HDL:LDL
b/c CHD leading cause of death in postmenopausal women |
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what are the major forms of HRT that use estrogen?
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1. estrogen only
2. estrogen + progest or synthetic progestin Typcially: No hysterectomy--estr and prog hysterectomy--estr only |
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why is progestin give along w/ estrogen in HRT?
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to prevent hyperplasia of cells in uterine lining (assoc. w/ uterine cancer)
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how is HRT scheduled?
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1. cyclic sequential use: estrogen daily w/ progestin 2 wks/month
2. contin. combined: estr and progestin daily |
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what did the big HRT studies find wrong w/ long term therapy?
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studies stopped b/c:
1st found increased risk breast cancer, heart attack and stroke then found no protection over CHD also found 2x increased risk of blood clots |
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what kinds of benefits were seen w/ the HRT trials?
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decreased risk of Colorectal cancer
decreased risk of fractures no difference in total deaths or cancer rates. |
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whats the effect of HRT on memory?
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2x increase in dementia (includes AD)
no protection against mild cognitive impairment (may have increased risk) |
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given, the risk/benefit of HRT, how should this therapy be used?
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risk/benefit specific to pt (e.g protection from bone fracture)
use lowest dose for least time use local administration if possible use alternate therapies |
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what are bio-identical hormones?
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naturally occuring from plants and fungi:
flavones isoflavones coumestan derivatives increased use due to fear of HRT no FDA regulation |
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what are the 2 major types of contraceptive therapy?
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type 1: COC--combined oral contraceptives?
type II: progestin alone (mini-pill or long acting implant) |
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what are combined oral contraceptives (type I: COC)?
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estrogen w/ progestin
(methyoxyprogesterone acetate) taken for 21 days then 7 off days |
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how do COCs work?
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progestin inhibits LH which prevents ovulation and inhibits implantation
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what are some different kinds of dosing regimens for COC?
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monophasic: fixed dose for 21 d
biphasic: fixed estrogen/ increase progestin dose triphasic:vary both est/prog |
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what are the adverse effects of taking combined oral contraceptives?
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weight gain, nausea, mood change, skin pigment
small incr thromboembolic dz (MI, stroke increase risk) small incr risk breast cancer? |
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what are the positive effects of using a combined oral contraceptive?
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progestin protects the endometrium of uterus from proliferative action of estrogen
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how does type II contraception compare to COC?
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less reliable than COC
disturbances in menstruation |
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what effect do antibiotics have on both type I and II contraceptive use?
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less effective w/ antibiotics like penicillins and tetracyclins
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what's nuva ring?
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1st hormonal vaginal contraceptive ring
release continous low dose progestin and estrdiol for 3 wks |
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what's ortho evra?
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1st hormonal contraceptive skin patch
replace 1x/wk uses H's: norelgestromin and ethyinyl estradiol |
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what's the buzz about yasmin (drospirenone)?
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a progestin that resembles a diuretc (no bloating or water retention)
"diet pill" |
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what's Plan B (levonorgestrel)?
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2 0.75 mg progestins w/in 72 hrs (doses 12 hrs apart)
or combo 4 pills (.25 mg levon and .05 mg estradiol) NOT RU486 (abortion pill) won't work if you're already pregnant |
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RU486
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mifepristone:
approved 2000 by FDA derived ffrom norethindrone emerg contracep to inhib ovulation or prevent implantation use <49 days from last cycle |
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where does mifepristone bind?
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RU486:
high-affinity anatagonist at both PR and GR |
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when can RU486 be taken ?
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mifepristone:
use up to 49 days from beginning of last menstrual period used as emerg contracept to inhibit ovulation or prevent implantation |
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what are the protective effects of contraceptives?
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decrease:
incidence of ovarian and endometrial cancer (50% after 2 yrs; protective up to 15 yrs after cessation) ovarian cysts, fibrocystic breast dz menstrual blood loss also: more regular less iron defic anemia less premenstrual tension less dysmenorrhea |
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why has breast cancer increased?
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genetic and environmental factors
1:8 women who live to age 85 get breast cancer 50% affected have NO risk factors |
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why do pesticides like DDT cause increased risk of breast cancer?
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they are estrogenic mimetic compounds (polycyclic w/ phenolic ring)
buildup in environment, accum in adipose |
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what drug is used for the treatment of metastatic endometrial cancer?
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medroxyprogesterone acetate ( a progestin)
50% of pts improve (younger=better prog) |
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what cancers do progestins treat?
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1st line: medroxyprogesterone acetate for metastatic endometrial cancer
2nd line: metastatic, H dependent breast cancer inhibits PR synth and ER synth |
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what's the mechanism by which progestins are useful in the treatment of breast and endometrial cancer?
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progesterone inhibits PR and ER synthesis
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what effect do SERMs have on receptors?
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inactive or weakly active/ compete for receptors
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what effects does tamoxifen have?
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nonsteroidal/estrogenic on plasma lipids, endometrium, and bone
upregulates TGFbeta recent approval for prevention in high-risk pts |
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what are new analogs of tamoxifen (SERMs)
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doloxiphene (breast cancer) and
raloxifene for osteoporosis: agonist in bone Antagonist in uterus and breast |
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what are some of the major effects of tamoxifen?
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inhibit prolif of breast cells in vitro
reduce tumor size stim endometrial cell (thickening) decr total chol and LDL (no incr HDL) prevent bone loss |
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S/E of using tamoxifen?
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2-3x incr in DVT risk, PE
cataracts, nausea, vaginal dryness, hot flashes muscle cramps |
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PK of tamoxifen?
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2 elimination phases:
7-14 hrs then 4-11 days (3-4 wks ot steady state) excretion in feces |
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what happens w/ long term tamoxifen tx?
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decreased efficacy after 5 yrs
acquired drug resistance (resistant tumors?) |
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how did raloxifene compare to tamoxifene in prevention of breast cancer?
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both lowered risk by ~50%
raloxifene had fewer uterine cancers and fewer blood clots (both increase clot risk though) |
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who are aromatase inhibitors used for?
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anastrozole/letrozole:
postmenopausal women after tamoxifen, aromatase inhibs signif improve dz free survival |
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what is 1st line tx in postmenopausal women to prevent breast cancer?
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aromatase inhibitors:
steroidal--irreversible (exemestane) non-steroidal--reversible (anastrozole, letrozole) |
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what can be coadministered w/ aromatase inhibitors in postmenopausal women to decrease bone loss?
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alendronate (Fosamax); biphosphonate that slows bone breakdown
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what kinds of memory deficits does anti-estrogen tx cause?
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decrease verbal memory
future drugs: won't x BBB |
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what are SERDs?
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selective estrogen receptor downregulators:
fulvestrant--antagonize estrogen by downreg both PR and ER) high affinity antag w/o effect impairs dimerization--promotes degradation |
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advantages of SERDs?
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fulvestrant:
no x-resistance w/ other tx's as effective as aromatase inhibs in postmenopausal women use when other tx become resistant |
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what kinds of therapy is there for infertility?
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clomiphene:
non-steroidal fertility agent acts at hypothal and pituitary blks feedback inhib of gonadotropin secretion inhibits: estrogen binding in pit (partial agonist induces ovulation |
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what happens when E2 binds the intracell ER?
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Hsp90 dissociates
E2 bound to ER causes conformational change and receptor dimerization goes to nucleus to interact w/ ERE (w/CoA) leading to target gene activation |
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how do SERMs interact w/ the ER's?
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selective for different ER's producing differential effects:
antagonism: ER dimer interacts w/ ERE to cause target gene repression agonism: ER interacts w/ Jun-Fos to AP-1 on DNA to cause target gene activation |
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what are the different activities of ER subtypes?
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alpha=active tsc
beta=low rate of tsc bind EREs w/ similar affinity differences in the recruitment of cofactors |
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what are the antiestrogen's effects on different ER subtypes?
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tamoxiphen, raloxifene, etc
alpha=partial agonist beta=pure antagonist |
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how do different ligands affect the hormone/receptor complex in the nucleus?
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differ in length of time:
estriol (1-4 hrs) estrone/estradiol/DES (6-24 hrs) tamoxifen (24-48 hrs) |
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which cells in males produce testosterone?
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interstitial cells of Leydig
sertoli cells support spermatozoa |
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what's the precursor to testosterone?
what is testosterone converted to? |
its interconvertible w/ androstenidione (made from DHEA by 3-b-dehydrogenase)
converted to DHT by 5a-reductase or to estradiol by aromatase |
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what are some of the therapeutic uses of androgen therapy?
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1. replacement therapy (sex maturation, traumatic bone loss, libido loss
2. infertility 3. breast and prostate cancer 4. male pattern baldness |
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where besides the testis is testosterone found?
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small amt in ovary
adrenal cortex of m/f |
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what controls adrenal production of androgens?
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corticotropin
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what are the precursors of androgens?
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epiandrosterone and androstenedion
also released from gonads from adrenal cortex converted to testosterone in liver |
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what do androgens produce?
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rapid devel of secondary sex charact (maturation of reprod organs, incr musc strength, hypertrophy of vocal cords, libido; tx of hypogonadism)
in females: masculinization Low D for HRT?? |
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how is testosterone given?
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subcut implant or testosterone esters like testosterone propionate (readily hydrolyzed)
given orally as methyltestosterone |
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adverse effects of androgens?
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infertility (inhib hypo-pit axis)
adenocarcinoma of liver; jaundice children-growth disturbances, acne feminization in M/F (aromatization to estradiol) decreased HDL:LDL ratio |
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what are the effects of anabolic steroids?
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increase muscle develop: wt gain
stanozolol nandrolone |
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what does chronic use of anabolic steroids lead to?
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MI and sudden death
potential for abuse (much larger dose then for replacement therapy) testicular atrophy, sterility, alopecia, acne, aggression, psychosis |
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how common is prostate cancer?
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2nd most common solid tumor and cause of death in US
about 30,000 deaths/yr still |
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how are estrogens and progestins useful for prostate cancer?
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they have antiandrogen activity by inhibiting release of gonadotropins (FSH, ICSH)
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antiandrogens useful for prostate cancer?
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cyproterone acetate: partial agonist of androgen R w/ weak progesterone activity to suppres gonadotropin release at Pit.
used w/ leuprolide=GnRH to inhibit release at hypoth |
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how does flutamide work?
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inhibits release of ICSH, LH
nonsteroidal tx for prostate cancer binds androgen R combined tx w/ GnRH agonist (leuprolide and histrelin) only showed 2.9% survival incr |
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how does finasteride (Propecia) work?
|
inhibits (100x) 5a-reductase II (isoenzyme I - 3x)
prevents high-affin androgen dihydrotestosterone (5-HT) production |
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what's the problem w/ finasteride?
|
tumor incidence increase
sexual side effects and urinary S/E's prevents/delays appearance of prostate cancer at high risk of urinary problems and sexual S/E's also, incr risk HIGH grade prostate cancer |
