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Steroids: Estrogen
and Progestin
Jennifer Kettel
Professor John Buynak
CHEM 5398
March 27, 2007
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Introduction
Estrogens
Progestins
Hormone ContraceptivesCombination Contraceptives
Progestin-Only Contraceptives
Emergency Contraceptives
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Estrogens and Progestins Estrogens and progestins are hormones that produce many physiological
actions
In women,
Developmental effects (estrogens are largely responsible for pubertalchanges in girls and secondary sexual characteristics)
Neuroendocrine actions involved in: Control of ovulation and thepreparation of the reproductive tract for fertilization and implantation
Major Actions on: Minerals, Carbohydrates, Proteins, and LipidMetabolism
In men, effects:
Bone Spermatogenesis
Behavior
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Estrogens A group of steroid hormones that readily diffuse across the
cell membrane
Inside the cell, they interact with estrogen receptors
Estriol Estradiol Estrone
AA A
D D D
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Estrogen Synthesis
Estrogen is produced primarily by developing follicles in the
ovaries, the corpus luteum, and the placenta
Follicle-stimulating hormone (FSH) and luteinizing hormone (LH)
stimulate the production of estrogen in the ovaries
Some estrogens are also produced in smaller amounts by
other tissues such as the liver, adrenal glands, and the breasts
The ovaries are the principal source of circulating estrogen in
premenopausal women, with estrodiol being the main
secretory product In postmenopausal women, the principal circulating estrogen
estrone, which is synthesized from dehydroepiandrosterone
and secreted by the adrenals
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Estrogen Synthesis
The most potent naturally occurring estrogen in humans forboth the Estrogen Receptor alpha- and beta-mediatedactions is 17beta-estradiol, followed by estrone and estriol
Each estrogen contains a phenolic A ring with a hydroxyl
group at carbon 3 and a beta-OH or ketone in position 17of ring D
The phenolic A ring is the principal structural featureresponsible for selective, high-affinity binding to bothreceptors
Synthesis of estrogen begins from the synthesis ofandrostenedione from cholesterol
Androstenedione crosses the basal membrane intosurrounding granulosa cells, where its converted to estroneor estradiol wither immediately or through testosterone
The conversion is catalyzed by aromatase
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Biosynthetic Pathway
This figure shows themajor metabolicintermediates in theusual synthesis of
estrogen, startingwith cholesterol,proceeding topregnenolone, an
androgen, and thenestrogen.
http://www.chemistryexplained.com/Di-Fa/Estrogen.html
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Estrogen Receptors
Estrogens exert their effects by interaction with receptors that aremembers of the super family of nuclear receptors
The two estrogen receptor (ER) genes are located on separatechromosomes: ESR1 encodes ER-alpha and ESR2 encodes ER-beta
Both ERs are estrogen-dependent nuclear transcription factorsthat have different tissue distributions and transcriptionalregulatory effects on target genes
Both ERs are ligand-activated transcription factors that increaseor decrease the transcription of target genes
After entering the cell by passive diffusion through the plasmamembrane, the hormone binds to an ER in the nucleus
In the nucleus, the ER is present as an inactive monomer boundto heat-shock proteins, and upon binding estrogen, a change inER confirmation dissociates the heat-shock proteins and causesreceptor dimerization, which increases the affinity and the rate of
receptor binding to DNA
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Anti-estrogens and SERMs
Anti-estrogens Pure antagonists
Clomiphene is fortreatment ofinfertility inanovulatorywomen
Fulvestrant is usedfor the treatmentof breast cancer
Selective EstrogenReceptor Modulators(SERMs)
Compounds withtissue-selective actions
The goal of these drugsis to producebeneficial estrogenicactions in certaintissues (ex. Brain, bone,liver) duringpostmenopausalhormone therapy
Tamoxifen, Raloxifen,
Toremifine
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Progestins Progestins include the naturally occurring hormone
progesterone, 17-acetoxyprogesterone derivatives in thepregnane series, 19-nortestosterone derivatives (estranges), andnorgestrel and related compounds in the gonane series
progesterone 17-acetoxyprogesterone19-nortestosterone
norgestrel
levonorgestrel
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Physcical Actions of Progesterone
In the reproductive tract, progesteronedecreases estrogen-driven endometrialproliferation and leads to the development of
a secretory endometrium The abrupt decline in progesterone at the end
of the cycle is the main determinant of theonset of menstruation
Progesterone is very important for themaintenance of pregnancy
It suppresses menstruation and uterinecontractility
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The Progestin ReceptorUnlike the ER receptor, which requires a phenolic ring for
binding, the PR favors a non-phenolic ring structure
There is a single gene that encodes two isoforms of the
progesterone receptor (PR): PR-A and PR-B
Since the ligand-binding domains of the two PR isoforms areidentical, there is no difference in ligand binding
However, the biological activities of PR-A and PR-B are
distinct and depend on the target gene in question
PR-B mediates the stimulatory activities of progesterone
PR-A strongly inhibits this action of PR-BUpon binding progesterone, the heat-shock proteins
dissociate, and the receptors are phosphorylated and
subsequently form dimers (homo- and hetero-) that bind with
high selectivity to progesterone response elements located on
target genes
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Anti-progestins Anti-progestin, first discovered in
1981, is mifepristone, used toterminate pregnancy
In the presence ofprogesterone, mifepristone actsas a competitive receptorantagonist for bothprogesterone receptors
When administered in the earlystages of pregnancy,
mifepristone causes decidualbreakdown by blocking uterineprogesterone receptors, whichleads to detachment of theblastocyst, decreasing hCGproduction
Mifepristone
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HormonalContraceptives
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Brief History
At the beginning of the 20thcentury, European scientists(Beard, Prenant, and Loeb)developed the concept
that secretions of thecorpus luteum suppressedovulation duringpregnancy
By the 1930s, scientists hadisolated and determinedthe structure of the steroidhormones and found thathigh doses of androgens,estrogens or progesteroneinhibited ovulation
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History cont.
In June 1957, the FDAapproved Enovid 10mg formenstrual disorders
Later, in May 1960, the FDAapproved Enovid forcontraceptive use
Although the FDAapproved this drug for
contraceptive use, it wasnot available to marriedwomen in all states until1965 and unmarriedwomen in all states until1975
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Types of
Hormonal
Contraceptives
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Combination
Contraceptives This type is the most frequently used in the United
States, which contain both an estrogen and a
progestin The theoretical efficacy is 99.9%
Ethinyl estradiol (a synthetic estrogen) andmestranol are the estrogens most frequentlyused
Levonorgestrel is the most common progestinused worldwide
Currently, this type of contraceptives havelowered doses of estrogen (low-dose)
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Forms of Combination
Contraceptives The Pill
The Patch
Vaginal Ring
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Combination
Contraceptives Mechanism of Action
Act by preventing ovulation
Measurements of plasma hormone levelsindicate that LH and FSH levels are suppressed
The mid-cycle surge of LH is absent
Endogenous steroid levels are diminished
Thus, ovulation does not occur
The multiple actions of estrogens and progestinson the hypothalamic-pituitary-ovarian axisduring the menstrual cycle and the efficacy ofthese agents all contribute to the blockade of
ovulation
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Progestin-Only Contraceptives
They contain progestins only,termed mini pills
Slightly less effective, with99% efficacy
Forms Pills
Injectables
Their effectiveness is thoughtto be due largely to a
thickening of cervicalmucus, which decreasessperm penetration andimpairs implantation
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Emergency Contraceptives The FDA has approved two preparations
PLAN-B includes 2 doses of levonorgestrel separatedby 12 hours (progestin-only)
PREVEN is a 2 pill dose of a high-dose oralcontraceptive (levonorgestrel and ethinyl estradiol)separated by 12 hours
The first dose of these drugs should be taken 72 hoursafter intercourse
PLAN B
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Emergency Contraceptives
Multiple mechanisms are likely to contribute to the efficacy ofthese agents, however, the exact mechanism is unknown
These mechanisms include:
Ovulation is inhibited or delayed, alterations in endometrial
receptivity for implantation Interference with functions of the corpus luteum that maintain
pregnancy
Production of a cervical mucus that decreases spermpenetration
Alterations in tubular transport of sperm, egg, or embryo Effects on fertilization
Emergency contraceptives do not interrupt pregnancy afterimplantation
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Side Effects
Many side effects were found to be dose
dependent, hence the development of the current
low-dose preparations
Side effects include: Cardiovascular effects (hypertension, myocardial
infarction, hemorrhagic stroke, venous thrombosis)
Breast, Hepatocellular, and Cervical Cancers
Endocrine and Metabolic effects Currently, its found that the low-dose preparations
pose minimal health risks in women who have no
predisposing risk factors
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Male Birth Control?
Current research and developmentis in various stages, some which
include A male version of the pill
A male hormonal contraceptiveimplanted under the skin
A drug which interferes with thematuration of sperm in the epididymis
Plugs that block the vas deferens