Term
what's wrong with estradiol?
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Definition
oral bioavailability is low b/c of first pass metabolism, need to modify structure
first pass: 3 reactions will effect estradiol (hydroxylation, COMT, and conversion to estrone and estriol)
have to block positions that are susceptible to metabolism (17, 3)
position 3 is not directly effected, but if you change 3 it changes the hydroxylation of ring A
3 and 17 can also be glucuronidated |
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Term
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Definition
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ethinyl estradiol, mestranol, and estropipate are analogs of estradiol
ethinyl estradiol: an ethinyl group was put at position 17 (alpha); 17 alpha is at a site of receptor interaction, but small groups can be put in this position; retain all activity of estradiol
mestranol: ether at position 3 (protection from metabolism), 17 alpha ethinyl group
estropipate: sulfate at position 3 and an analog of estrone b/c of keto group at 17
chlorotrianisene and dienestrol are non-steroidal estrogens, mainly used for the treatment of cancer and osteoporosis
ESTERS
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esters are used parenterally mainly to act as a slow release (long acting estrogens)
2 positions can be esterified: 3 and 17 oxygen groups
CONJUGATED ESTROGENS
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conjugated estrogens are isolated from pregnant horses
called conjugated estrogens because there are more double bonds than in the endogenous estrogens (ring B) |
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Term
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Definition
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ester derivatives -> prolonged action
ether derivatives: oral vs. subcutaneous
used to improve oral bioavailability of the analogs, ethers can also be used subcutaneously
substituents at 6, 7, and 11 decrease activity, but do not completely lose activity
oxygen at position 3 and 17 IS REQUIRED
distance between O of 3 and 17 is what is important
ring expansion is not allowed b/c the distance between these O groups have to be the same as estradiol
conformation of 17-OH is important (b/c of distance); HAS TO BE BETA!
the double bonds at ring B INCREASE THE AFFINITY to the receptor |
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Term
| non-steroidal estrogen receptor ligands |
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Definition
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these compounds are very toxic and have preferences to either the alpha or beta estrogen receptors
can be agonists or antagonists |
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Term
| antiestrogens: triphenylethylene analogues |
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Definition
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raloxifene and tamoxifene are most commonly used
triphenylethylene analogs:
structurally related to the stilbene family
high affinity for estrogen receptor
they prevent translocation of the estrogen receptor complex into the nucleus of the target cell
interfere with the binding of the estrogen receptor complex |
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Term
| antiestrogens: aromatase inhibitors |
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Definition
NON-STEROIDAL AROMATASE INHIBITORS
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STEROIDAL AROMATASE INHIBITORS
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IMPEDED ESTROGENS
estrone is converted to estradiol and estradiol is converted to estrone
impeded estrogens can impede the actions of estradiol
high concentrations of estrone can impede the action of estradiol by interacting with the receptor instead of estradiol
estrone or estriol can impede the action of estradiol because they are less potent
estrone and estriol have low affinity for the estrogen receptor (will dissociate fast), if there are high concentrations of estrone and estriol they will go in and out of the receptor without causing any effect = antiestrogen
aromatase inhibitors are also antiestrogens:
the aromatase enzyme converts androgens into estrogens
testosterone and androstenedione are the 2 androgens that are converted into estrogens through aromatase enzyme
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steroidal inhibitors compete mainly with androstenedione
the non-steroidal aromatase inhibitors mainly inhibit the conversion of testosterone to estradiol
(blue is androstenedione) |
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Term
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Definition
progesterone cannot be administered orally due to first pass metabolism
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progesterone also can have some androgenic effects (androgens can look like progesterone)
most of the progestins have affinities for the other steroidal receptors (estrogens, glucocorticoids, mineralocorticoids, and androgens)
most of the progestins will be anti-estrogenic, some will have androgenic effects
4th generation progestins: no androgenic effect and some anti-androgenic effects, no glucocorticoid effects and some have anti-mineralocorticoid effects |
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Term
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Definition
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rationale behind these analogs:
R1 is at position 6 (here hydroxylation can occur)
R2 is position 17 (the reduction is at position 20, but the groups that are added here can block the reduction of 20)
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main features of these structures:
ethinyl group at position 17 alpha
many do not have carbon 19, don't need the 21 carbon backbone
some have a beta OH group at position 17
ethynodiol diacetate is a prodrug
levonorgestrel has an ethyl group at 13
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4th generation: show less androgenic activity or no androgenic activity
progestins are flexible in terms of what can be done with the molecule
sp2 carbon in ring B and C is acceptable
oxygen functionality at position 17 is better if it is BETA
can have a small group substitution at position 17
nomegestrol and drospirenone can be hydrolyzed by esterases
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levonorgestrel related analogs
these analogs get converted in vivo to levonorgestrel (except desogestrel; ethylene group at position 11) |
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Term
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Definition
ONLY steroidal compounds
(androgens only had steroidal compounds also)
(the only compounds that have non-steroidal structures with affinity are the estrogens)
17 alpha hydroxyprogesterone and androstanes
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many of the progestins have androgenic activity b/c of the androstane backbone (others have 17 alpha hydroxyprogesterone as a backbone) |
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Term
| progestin analog metabolism |
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Definition
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those that have a carbonyl may be reduced to a hydroxy
the 4-5 double bond can be reduced to the alpha or beta H
FOR ALL STEROIDS 5-beta does not have any activity |
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Term
| steroidal progesterone receptor ligands SAR |
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Definition
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Ring A:
keto group is good
OH groups also have good progesterone activity and less anabolic activity
Ring B:
double bond is acceptable
substitution at 6 and 7 are acceptable
Ring C:
can tolerate double bonds (especially between 9 and 10; can be thought of as a double bond in ring B)
substitution at 11 is tolerated (as long as it is a small group; bigger groups makes it antiprogestin)
Ring D:
double bonds tolerated, substitutions tolerated
carbon 20 and 21 can be eliminated or replaced whild retaining progesterone activity
at position alpha ethinyl groups are good
small groups at position alpha are acceptable
19-norprogesterone shows better progesterone activity
elimination of carbon 19 INCREASES PROGESTERONE ACTIVITY
aromatic rings are not tolerated |
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Term
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Definition
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steroidal type structures with large groups at position 11
MOA: bind to the progesterone receptors and do not produce any activity
compete with progesterone for the receptor and do not cause activity
metabolism: N-demethylation, hydroxylation of the terminal carbon group of mifepristone |
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Term
| therapeutic applications of female hormone derivatives |
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Definition
contraceptives
endometriosis:
combination oral contraceptives
gonadotropin releasing hormone agonists: leuprolide, goserelin, and nafarelin
androgenic agents: danazol
progestins
aromatase inhibitors
SERMs
progesterone receptor modulators
surgical intervention
infertility:
estrogen agonists
GnRH agonists
FSH
dopamine agonists
menopause:
hormone replacement therapy
osteoporosis
hormone dependent breast cancer:
SERMs
antiestrogens
aromatase inhibitors |
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Term
| what is the role of estrogens in the menstrual (reproductive) cycle? |
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Definition
estrogens are related to FSH
estrogens will regulate FSH |
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Term
| what is the role of progesterone in the menstrual (reproductive) cycle? |
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Definition
progesterone is related to LH
progesterone will regulate LH |
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Term
| what is the role of FSH in the menstrual (reproductive) cycle? |
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Definition
| maturation of the follicles |
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Term
| what is the role of OH in the menstrual (reproductive) cycle? |
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Definition
| ovulation, formation of the corpus leutium |
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Term
| what is the role of estrogens in combination oral contraceptives? |
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Definition
| suppress FSH and the maturation of the follicle |
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Term
| what is the role of progestins in combination oral contraceptives? |
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Definition
| suppress LH to prevent ovulation |
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Term
| monophasic vs. multiphasic contraceptives |
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Definition
multiphasic: follow fluctuating hormone levels of a normal cycle
monophasic: have the same level of estrogen and progesterone concentration |
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Term
| glucuronide conjugation of sex hormones |
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Definition
glucuronide conjugation leads to the termination of effects
O-glucuronide conjugates are less active or inactive
bioavailability-limiting glucuronide conjugation is always a drug design consideration
increases solubility and is eliminated
net glucuronidations: the rate at which the drug is glucuronidated; the rate the drug is used and the rate the drug is recovered
glucuronidase (gastric mucosa and hepatocyte endoplasmic reticulum) - enzymes that break the bond and turn the drug back into the parent drug (active again)
glucuronidases are very susceptible to steric hindrances (rate of recovery of the drug)
structure and access
susceptibility to glucuronidation is dependent by: rate of glucuronidation by uridine dephosphate and degree of exposure of the conjugate to glucuronidase
enterohepatic recycling:
bacterial hydrolases
glucuronide conjugates are accumulated in the bile duct and transported into the small intestine
conjugates are substrates for bacterial hydrolases
it accounts for prolonged duration of effects and antibiotic interactions
bacteria break the conjugates and free the parent drugs
antibiotics will decrease normal flora and suddenly there will be less concentration of estrogen hormones |
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Term
| pharmacological approach to infertility |
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Definition
stimulation of ovulation:
clomiphene citrate (clomid)
human chorionic gonadotropin
human menopausal gonadotropin
follicle stimulating hormone
dopamine agonists
gonadotropin releasing hormone (agonists and antagonists)
lutropin alfa |
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Term
clomiphene citrate
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Definition
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mixture of 2 geometric isomers:
Z (cix): estrogenic activity
E (trans): anti-estrogenic activity
stimulation of ovulation:
it blocks estrogen receptors in the hypothalamus inhibiting the natural feedback -> secretion of GnRH -> release of FSH and LH -> promotion of follicular development -> secretion of estradiol
administered orally:
five days on days 5 to 9 of menstrual cycle
estradiol levels are detected by the hypothalamus -> pituitary secretes LH
ADRs:
thickening of the crevical mucus
endometrial thinning
hot flashes and mood swings |
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Term
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Definition
human chorionic gonadotropin:
mimics LH
administered to stimulate a scheduled ovulation
human menopausal gonadotropin:
composed of equal parts of LH and FSH
they directly stimulate the ovaries to develop multiple follicles
FSH:
stimulate the development of multiple follicles |
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Term
| gonadotropin releasing hormone |
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Definition
primary role: prevent a premature surge of LH
AGONISTS:
administered continuously to hyperstimulate the pituitary
agonists cause FSH and LH to increase
surge of FSH and LH, but after that, it stops b/c of the feedback system
steroidal hormones increase, then decrease after feedback kicks in
once the hormones stop, the doctor is in control of the cycle and can more easily control ovulation
know exactly the days to administer other hormones to make the eggs more vital
ANTAGONISTS:
used in the same way but they have the advantage that they don't produce a surge, they just cause the hormones to stop
agonists have a big surge then stop hormones
antagonists just stop the hormones
once you stop the natural hormones, you can manipulate the hormones yourself |
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