Steroids JenniferKettel

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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

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