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30 Cards in this Set
- Front
- Back
What is the most important of oestrogens? (3)
what controls it? how is it synthesized (3) |
• 17B-estradiol (active), estrone & estriol (less active)
• FSH: regulates synthesis & secretion Synthesis • precursor: testosterone, • key enzyme: aromatase • metabolism of 17B-estradiol to estrone & estriol |
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where are estrogens produced? (5)
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• ovaries: estradiol
• ovarian follicles (before ovulation); • corpus luteum (after ovulation) • placenta (pregnancy) • estrone & estriole in liver/peripheral tissues, from estradiol |
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mechanism of action of estrogens
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Estrogen + ER (of superfamily of nuclear receptor) ->
ER conformation change -> translocation to nucleus -> bind to estrogen response element in target gene -> recruit co-activators -> initate gene transcription -> specific hormonal effect Antagonist: same process as estrogen, except co-repressors (not co-activators) recruited, and gene transcription is REDUCED. |
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admin (5)/absorption of estrogens (1)
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• estradiol: 1st pass (low bioavail. & hepatic effects): micronized prep for rapid absorption post oral intake
• ethinyl estradiol: reduce 1st pass • conjugated equine estrogen: sulfate esters of estrone/other estrogens, metabolized to active form • IM: aqueous & oil-based preparations • transdermal: slow sustained, avoid 1st pass • enterohepatic recirculation: conjugation in liver -> excrete into intestine -> hydrolysed in gut -> reabsorb |
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effect of estrogens (4)
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- female repro/breast tissues
- bone: +ve effect on bone mass. ↓osteoclast apoptosis, ↓resorption of bone - Lipids: ↑HDL, ↓LDL; ↑synthesis of TG - Coagulation: ↑clotting factors (hepatic coagulation) |
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limitations of estrogens (related to dose) (4)
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- stimulate endometrial growth (risk: hyperplasia, ↑uterine bleeding risk)
- ↑ Ca breast, Ca endometrium - ↑ thromboembolism - nausea, breast tenderness, migraine, HT |
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clinical uses of estrogens (6)
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- replace estrogen deficiency (failed ovaries, menopause)
- primary hypogonadism - development of sec. sexual characteristics (11-13 y/o) - stimulate growth & bone development - Progestin/birth control/HRT - tx osteoporosis |
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what are SERM (selective estrogen receptor modulators) and anti-estrogenic:
- examples of both (3 SERM, 2 anti) |
- SERM: tamoxifen, raloxifene, toremifene
- anti-estrogens: clomiphene, fulvestrant |
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Tamoxifen
what is it (1) clinical uses (2) limitations (1) side effect (4) |
- partial agonist/inhibitor of ER
- tx & chemoprevention of Ca breast in high risk grp. - reduce contralateral ca breast - no further improvement after 5 yrs - SE: hot flush, nausea, vomiting, infertility |
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Raloxifene
properties (3) clinical uses (2) |
- parial estrogen agonist/antagonist (SERM) in SOME target tissue
- effects similar to estradiol on lipids/bones - NO effect on breast & endometrium - prevent osteoporosis in postmenopausal - prophylaxis of ca breast in high-risk ♀ (less useful than tamoxifen) |
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fulvestrant's properties (2)
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- pure anti-estrogen
- tx tamoxifen resistant ca breast |
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estrogen synthesis inhibitors (2)
examples (3) |
- aromatose inhibitor
(↓estrogen ∵ aromatose in synthesis of estradiol) - Tx Ca breast - exemestane, letrozole, anastrozole |
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Progestins:
most important controlled by? produced by? (2) levels (3) |
- progesterone
- LH: regulates synthesis and secretion - corpus luteum. placenta in pregnancy - low level in follicular phase, higher level in luteal phase much higher during pregnancy |
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mechanism of action of progestins (3)
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- PR (superfamily of nuclear receptor: PR-A, PR-B)
- hormone + PR -> PR conformation change -> dimer -> translocation to nucleus -> bind to prog. response element (in target gene) -> recruit co-activator/co-repressor -> modify gene transcription -> specific hormonal effect - PR-A or PR-B + coactivators & corepressors -> various effects (↑/↓ gene transcription) |
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admin (3)/absorption (4)
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- ester: ↓hepatic metabolism
- oil-based: for IM injection - implants/depot: slow release (long-term tx) - 1st pass of progesterone: low bioavailability, hepatic effects (micronized prep for rapid absoprtion) - free progesterone elimination t1/2: 5 minutes - highly protein bound -> longer half-defect - synthetic progestins: similar effect to progesterone |
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effects of progestins (3)
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- luteal phase of menstrual cycle
- Repro: maintain pregnancy, ↓ estrogen-stimulated endometrial proliferation - ↑LDL/↓HDL (opposite of estrogens on lipid profile) |
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clin uses of progestins (4)
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- contraceptin: alone, or with estrogen
- HRT in postmenopausal - abnormal uterine bleeding (↓estrogen's effect on endometrial growth & hyperplasia - palliative for metastatic ca endometrium |
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what are anti-progestins (2)
SE (1) |
mifepristone
- block uterine PR -> detach blastocyst -> ↓hCG -> ↓ progesterone by corpus luteum -> loss of blastocyst (can't maintain pregnancy) - mifepristone combined w. misoprostol (PG): termination of early pregnancy (misoprostol: contraction of uterus, expulsion of fetus) SE: vaginal bleeding |
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what are androgens:
- most important - regulation - levels in people - produced by |
- testosterone, dihydrotestosterone
- gonadotrophins (LH). *testosterone inhibits LH secretion in men - declines after 50 in men. - 95% Leydig cells of testis, 5% by adrenals - Testosterone -> DHT (5a-reductase) - Testosterone -> estradoil (aromatase) - smaller amount in women (frm ovaries, adrenals) |
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mechanism of action of androgens
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androgen receptor (nuclear):
testosterone & DHT major agonists for androgen receptor - Hormone + AR -> AR conf. change -> dimer -> translocation to nucleus -> bind to androgen response elemtn in target gene -> recruit co-activators/co-repressors -> initate gene transcription ↑/↓ gene transcription |
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admin (3)
absorption (2) of androgens |
- IM injection of ester form: hydrolysis to release testosterone. (bypass hepatic metabolism)
- alklyated androgens ↓ hepatic metabolism - transdermal delivery systems: patch, gel - absorb rapidly -> inactive (and some active) metabolites in liver - 1/6 avail. in active form: difficult to control amnt of active & inactive metabolites |
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effects of androgens
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anabolic effect
development/growth of male repro organs |
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clin uses of androgens (4)
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- androgen replacement tx in men: secondary sex characteristics -> puberty/enhance growth (use IM injection of long acting ester form)
- gynecological disorders: danazol for endometriosis, for chemo of ca breast in premenopausal - anabolic steroid/androgen abuse in sports (↑strength & aggressivness) - aging: ↑lean body mass & hematocrit, ↓bone turnover |
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anti-androgens (2)
describe them (2) |
Androgen receptor antagonists (flutamide etc)
-block testosterone receptor -> ↑LH secretion -> ↑testosterone -> counteract effect of antagonist - in conjunction w. blocking GnRH to tx Ca prostate 5a-reductase inhibitors (finasteride & others) - block coversion of testerone to dHT - treat BPH |
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why must we give postmenopausal hormonal therapy (what happens when you go on menopause) (3)
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After menopause: ↓female hormones by ovaries
- ↑bone loss, ↑fractures (vertebral, hip, wrist) - ↑plasma cholesterol (↑atherosclerosis, ↑CVS disease) - postmenopausal: hot flush, insomnia vasomotor sx, osteoporosis, vaginal dryness, UG atrophy |
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Give an example of HRT: (3)
are there any proven benefits? |
continuous/cyclic
- conjugated estrogens, MPA (medroxyprogesterone acetate) & other progestins - estrogen + progestin (menopausal, +uterus) - estrogen (menopause, hyster., no endometrial prob) - NO: small ↑Ca breast, ↑CVS disease. ↓Ca colon, ↓osteoporosis |
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what is homornal contraception (3)
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- producuing temporary, reversible state of infertility
- combined pill: estrogen-progestin - mini pill: progestin-only |
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describe hormone 'flow' of female repro system (5)
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Hypothalamus: GnRH ->
stimulate anterior pituitary: FSH, LH -> FSH stimulates Graafian follicle -> oestrogen LH stimulates corpus luteum -> progesterone oestrogen/progesterone inhibits ant. pituitary |
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admin (1) and MoA of combined pill (estrogen + progestin) (6)
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- take 21 consecutive days, with 7 day break
- ↑neg. feedback: selectively inhibit pituitary function - ↓FSH release: ↓development of ovarian follicle - ↓LH release: prevent ovulation - changes cervical mucus in uterus - change motility & secretion in uterus - ↓conception, implantation |
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admin (1) and MoA of progestin-only contra (3)
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continuously for 28 days, w/o break
- inhibit hypothalamus, slow frequency of GnRH pulse generator. Inhibits LH release; prevents ovulation - cervical mucus thickens, ↓sperm penetration - endometrial alterations, ↓implantation |