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Pharmacology II Block 3 Estrogens

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In high concentrations, estrogen may hit and activate which receptors?
Cortisol receptors
What is the main estrogen produced in pre-menopausal and menopausal women?
Estradiol (from the ovaries)
What is the main estrogen produced in post-menopausal women?
Estrone (from adipose tissue - DHEA from adrenals)
In males, where is estrogen produced?
Estrogens from the testes / Estrone/Estradiol from androstenedione and DHEA
What are the estrogens made in fetus/placenta?
Estrone and Estriol from DHEA
What enzyme converts androstenedione to estrone?
Aromatase
What are the steps in estrogen activation in the nucleus?
Estradiol (E2) enters the cell by passive diffusion / E2 binds to ERs (either alpha or beta) / ERs dimerize / Dimer binds to Estrogen Response Element on DNA / Transcriptional Activity Response (either inducer or repressor)
Where can estrogen receptors occur?
In the nucleus or on cell membranes
Where are ERalpha located?
Uterus, Ovaries, Vagina, Mammary Glands, Hypothalamus
Where are ERbeta located?
Ovaries, Prostate, Bone and Vascular Endothelial Cells
What is the physiological effect of estrogen in females?
Growth and development of the vagina, uterus, fallopian tubes, breast enlargement, bone growth/skeleton shaping, fat distribution, axillary and pubic hair growth, and pigmentation of genitals/nipples
Estrogen deficiency in males causes what?
Diminished pubertal growth spurt, delays in epiphyseal plate closure/skeletal maturation and in adult men, elevated gonadotropins, macroorchidism and increased testosterone levels
What is the main MOA of contraceptives?
Prevents ovulation by blocking normal release of GnRH, FSH and LH
What effect does estrogen have on the endometrium?
proliferation
What effect does progesterone have on the endometrium?
maturation
What causes a surge of LH in women on around Day 14 of their cycle?
the presence of estrogen
When should estrogen be given to block the release of LH/FSH that prevents the development of an egg?
early in the cycle
What is the main role of estrogen in increasing bone mass?
decreases the number and activity of osteoclasts
What effect does estrogen have on lipids?
Decreases total cholesterol, while increasing HDL and decreasing LDL
What population of women is at increased risk for gall bladder stones?
Four Fs - Female who is Forty (or over) and is still Fertile and who is Fat
How much effect does estrogen have on carbohydrates?
not much effect
What effect does estrogen have on proteins?
increases hormone-binding proteins, increases clotting and coagulation factors, but also increases anticoagulation factors too
How does estrogen have a vasodilating effect?
Decreases renin/ACE and also increases NO in vascular wall
What is the major urinary metabolite of estrogens?
Estriol
What is the main pathway of estrogen metabolism?
conversion to 2- or 4-hydroxycatechols by CYP1A and others which are then metabolized by COMT to 2- and 4-methoxyestrogens
What can also induce CYP1A metabolism of estrogens?
cigarette smoke
What are two essential SAR for estrogens?
aromatic A ring and a C3 hydroxyl
What are three important but not essential SAR for estrogens?
17beta hydroxyl or ketone, distance between C3 and C17 hydroxyl and presence of a planar hydrophobic scaffolding (benzene ring)
What SAR elements decrease the activity of estrogens?
functional groups at C1, OH at C6,7 or 8, Loss of C3 or C17 OH, epimerization of 17beta to 17alpha
What SAR elements increase the activity of estrogens?
addition of a C=C at C7, substitution at C11beta, 17alpha or 16, especially ethinyl or vinyl at 17alpha (decreases first-pass metabolism) and enlargement of the D ring
What are examples of naturally occurring steroid estrogens?
17beta estradiol, estriol, estrone, estrone sulfate and equilin sulfate
What are examples of synthetic steroid estrogens?
ethinyl estradiol, estradiol valerate, mestranol (prodrug that gets converted to ethinyl estradiol)
What are three non-steroid estrogenic compounds?
Diethylstilbestrol, Phytoestrogen and Bisphenol A
What non-steroid estrogenic compound is not used any more du to significant increase in uterine cancer?
Diethylstilbestrol
What non-steroid estrogenic compound is a plastizer that may contribute to early puberty in girls?
Bisphenol A
What is necessary for increased absorption of oral estrogen preps?
they need to be in a micronized form
What are some preparations of estrogens?
Oral, Transdermal Patch, Topical Cream, Vaginal Application (ring or tablet) and IM
What are three therapeutic uses for estrogens?
Oral contraceptive (when added with progestin), post-coital contraception (high dose of estrogen), menopausal therapy, and Failure of ovarian development (aka Turner Syndrome)
What type of therapy involves conjugated estrogens alone?
Estrogen Replacement Therapy for menopause
What type of therapy involves estrogens and progestins (the latter added to limit endometrial hyperplasia)?
Hormonal Replacement Therapy for menopause
What is a major therapeutic concern for estrogen use?
carcinogenic effects
What is the pharmacological goal of using Selective Estrogen Receptor Modulators?
Agonist action in certain tissues like the bone, brain and liver, but antagonist activity in other tissues like the breast and endometrium
What SERMs is approved for the treatment of breast cancer?
Tamoxifen and Toremifene
What SERM is approved for treatment of osteoporosis?
Raloxiphene
What are two examples of anti-estrogens?
Clomiphene and Fulvestrant
What is structurally unique about Tamoxiphen?
prodrug that is similar in structure to diethylstilbestrol
What isomer is Tamoxiphen predominantly marketed as?
Trans isomer
Which CYPs are involved in metabolism of Tamoxiphen?
CYP2D6 (important), CYP3A4 and CYP3A5
How does Tamoxiphen exert its pharmacological effect on breast cancer?
inhibits proliferation of cultured breast cancer cells (antagonist activity) and stimulates proliferation of endometrial cells (partial agonist activity)
What pharmacological activity does Raloxifene have?
partail estrogen agonist in bone but antagonist in endometrium and breast, reduces total and LDL cholesterol and has antiproliferative effect in ER+ breast tumors
What is one main thing to watch for with Raloxifene?
increases DVTs
What pharmacological activity does Clomiphene have?
binds to ERalpha and ERbeta to block estradiol binding, increases amplitude of LH and FSH secretion without changing pulse frequency by blocking inhibitory effect of estrogen
What is the therapeutic effect of Clomiphene?
induces ovulation in women with functional hypothalmic-hypophyseal-ovarian system and adequate endogenous estrogen production
What are examples of aromatase inhibitors?
Anastrazole and Letrozole / Emestane and Formestane
What do Anastrazole and Letrozole do as aromatase inhibitors?
competively inhibit aromatase enzyme and block synthesis of estrogens (reversible)
What do Emestane and Formestane do as aromatase inhibitors?
covalently bond to and inhibit aromatase (irreversible)
Even though aromatase inhibitors may be more effective than Tamoxiphene, what do they cause?
Osteoporosis
Where is progesterone made in females?
Pre-pregnancy - ovaries (corpus luteum) / Pregnancy - placenta (2nd or 3rd term) / Fetus - Fetal Adrenal Gland
How many progesterone receptors are there?
Two (PR-A and PR-B)
What is unique about the PR-A receptor?
It is shorter and is an inhibitor of PR-B
What is unique about the PR-B receptor?
It is longer and is the more important stimulator in most tissues
What is the MOA for progesterone?
Progesterone enters the cell and binds to the PR / PR dimerizes / Dimer interacts with a Co-activator or Co-repressor / Dimer+CoA (R) bind to Progesterone Response Element on DNA and activate/inhibit transcription of mRNA
What neuroendocrine action does progesterone perform?
decreases frequency of GnRH release by the hypothalamus
What reproductive tract activities does progesterone perform?
decreases estrogen-driven endometrial proliferation, causes maturation of the endometrium and suppresses menstruation and uterine contractility
What CNS effects does progesterone perform?
increases basal body temp about 1 degree F at midcycle
What metabolic effects does progesterone perform?
Increases LDL
Where is progesterone metabolized?
rapid first-pass metabolism in the liver (hydroxylated metabolites that are then sulfated or gluruonidated)
What are the three classes of progesterone-related compounds?
Pregnanes, Estranes and Gonanes
How are pregnanes absorbed?
poorly absorbed orally (low bioavailability)
What SAR occurs on pregnanes and to what effect?
adding an acyl group to C17 slows liver metabolism (OAc) / Adding CH3 to the C6 decreases metabolism
What SAR occurs on Estranes and to what effect?
Removal of the C19 CH3 (nor) maintains progestin activity and some androgenic effects / adding C17 alkynyl increases progestin activity and decreases metabolism
What SAR occurs on Gonanes and to what effect?
Change of C13 from CH3 to CH2CH3 reduces androgenic effect
What are some therapeutic uses for progesterone and progesterone-like compounds?
Menopausal Hormone Therapy, Regular Oral Contraceptives and Post-Coital Contraception
What two progesterone agents are used in menopausal hormone therapy?
micronized progesterone or medroxyprogesterone (MPA)
What progesterone agent is used as an oral contraceptive?
19-nortestosterone (estrane) or Norgestrel (levonorgetrel) in combo with estrogen (blocks ovulation)
What progesterone agent is used in post-coital contraception?
Levonorgestrel at higher doses (blocks LH surge and ovulation, prevents implantation)
What is the MOA for anti-progestins?
Decidual breakdown of uterine progesterone receptors / Detachment of blastocyst (implanted embryo) / Decreased hCG production and decreased progesterone production by corpus luteum / Increased prostaglandin production in uterus which sensitizes endometrium to contractile actions / Expulsion of blastocyst (embryo)
What is the therapeutic use for anti-progestins?
Abortifacient (RU-486)