Oral Oral ContraceptivesContraceptivesEstrogen and Progestin

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Hormones Hormones = “chemical messenger from one cell to another”

4 classes of Hormones• Amine Derived Hormones• Peptide Hormones• Steroid Hormones• Lipid and Phospholipid Hormones

Steroid Hormones-derived from cholesterol-primarily produced in adrenal cortex or gonads

Types of Steroid Hormones• Anabolic steroids • Corticosteroids• Sex hormones

Major steps in Steroid Hormone Binding

• http://highered.mcgraw-hill.com/sites/0072437316/student_view0/chapter47/animations.html#

cholesterol

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The Sex SteroidsThe Sex Steroids

• Female Sex Steroids Include:

Estrogens and Progestins

The most potent estrogen is estradiol.

• Male Sex Steroids Include:

Androgens

The androgen found in blood is testosterone.

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Female or Male?Female or Male?

• All three classes of endogenous steroids are present in both males and females.

• But, the production and circulating plasma levels of estrogens and progestins are higher in females and that of androgens are higher in males.

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Female Sex DriveFemale Sex Drive

• However, sexual desire in women is probably more dependent upon androgens, secreted by the adrenal glands and ovaries, than estrogen.

• Sex drive is maintained beyond menopause, a time when estrogen levels become very low.

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Interaction of Hormones Interaction of Hormones with Surface Proteinswith Surface Proteins

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OvulationOvulation• Follicular phase

– LH and FSH concentrations increase due to GnRH

– Follicular growth

– Antrum fluid volume increases

– Blister forms in ovary

• Ovulation Phase– Follicle released from

ovary secretes estrogen

– Corpus lueteum triggers release of progesterones and estrogens

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OvulationOvulation

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During PregnancyDuring Pregnancy

• The levels of estrogen and progesterone increase during pregnancy

• A good source of estrogens is the urine of pregnant women.

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History of Oral History of Oral ContraceptivesContraceptives

• 1937- discovery of effects of progesterone on ovulation

• 1940’s- Russell Marker isolates progesterone from Mexican yams

• 1951- Luis Miramontes synthesizes 1st progestin

• 1950’s: Studies show that the combination of an estrogen and a progestin prevents contraception.

• 1960- FDA approves “the pill”• 1963- 1st oral contraceptive put on drug market• 1965- number one form of birth control• Late 1970’s- FDA mandated warning that

indicated oral contraceptives carried risks of cancer and blood clots

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Uses of Oral Uses of Oral ContraceptivesContraceptives

• Primary Use– Prevent pregnancy

• Secondary Uses– Heavy or irregular menstruation– Endometriosis– polycystic ovary syndrome – dysfunctional uterine bleeding

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What’s in “The Pill”What’s in “The Pill”

• 20-40 micrograms ethinyl estradiol (synthetic form of estrogen)

• Varying amounts of either levonorgestrel or norethindrone as the progestagen component

• Types of Regimens – 21-day or 28-day pack

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Combined mode of Combined mode of action of estrogen and action of estrogen and

progestinprogestin• Prevents ovulation• Thickens mucous in cervix• Thins endometrium

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How does it work?How does it work?

• Estrogen and progesterone can inhibit pituitary gonadotropin release, thereby preventing ovulation.

• In practice, oral contraceptives, particularly the minipill (contains only progesterone-like substances), do not always prevent ovulation, but they are still effective because they have other contraceptive effects.

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How does it work?How does it work?

• Progestogens affect the composition of the cervical mucus, reducing the ability of the sperm to pass through the cervix.

• They also inhibit the estrogen-induced proliferation of the endometrium, making it inhospitable for implantation.

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Gonadotropin Gonadotropin Releasing Hormone Releasing Hormone

(GnRH)(GnRH)• Synthesized by hypothalamus • Stimulates anterior pituitary gland

to release FSH and LH• A decapetide (contains 10 amino

acids)pGlu-His-Tyr-Gly-Leu-Arg-Pro-Gly-NH2

• secretion begins at puberty

• Primary Effects– secretion of estrogen

and progesterone in females

– secretion of testosterone in males

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EstrogenEstrogen• Primary female sex hormone• Roles of estrogen:

– To develop secondary female sex characteristics

– Thicken the endometrium– Regulate menstrual cycle

• Regulation– Production of estrogen regulated by Follicle

Stimulating hormone (FSH) and Luetinizing hormone (LH), both produced in the anterior lobe of the pituitary gland

• Hypothalamus→GnRH→ Pituitary→FSH→Follicle→Estrogens

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Naturally occurring Naturally occurring estrogensestrogens

Estradiol

Estrone

Estriol

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Metabolism of Metabolism of Estradiol Estradiol

• Estradiol itself is not orally bioavailable, due to its rapid oxidation in the liver

HO

OH

Estradiol

HO

O

Estrone

Estradiol

Dehydrogenase

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Biosynthesis of Biosynthesis of estradiolestradiol

Testosterone

O

OH

Aromatase

Estradiol

HO

OH

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Synthetic EstrogensSynthetic Estrogens

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Synthetic EstrogensSynthetic Estrogens

• Note that the synthetic estrogens contain a tertiary alcohol, instead of a secondary alcohol.

• This tertiary acetylenic alcohol cannot be oxidized to the corresponding ketone, thus is metabolically stable, and orally bioavailable.

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Estrogen ReceptorsEstrogen ReceptorsTwo types of Receptors• ER alpha• ER beta

Mode of Action-1) Estrogen passes through

phospholipid bilayer2) Ligand binds in hydrophobic

region of receptor forming cap over ligand binding pocket

3) Estrogen and ER complex bind to estrogen response element in the nucleus to initiate transcription

4) Translation creates proteins which target various organs and processes in the female body

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ProgesteroneProgesterone• Produced by

– Adrenal glands

– Gonads

– Brain

– Placenta (only during pregnancy)

• Regulation- stimulated by the production of LH

• Hypothalamus→GnRH→ Pituitary→LH→Corpus luteum→Progesterone

• Primary Effect- prepares uterus for implantation by the proliferation of endometrium; prepares body for pregnancy

• Natural progesterone- destroys digestive system when consumed orally

ALL oral contraceptives contain progestin,

synthetic form of progesterone

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Conversion of Conversion of pregnenolone to pregnenolone to

progesteroneprogesterone

pregnenolone progesterone

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Metabolism of Metabolism of ProgesteroneProgesterone

• Progesterone itself is not orally bioavailable, partially due to its metabolism

Progesterone

O

O

OH

O

O

O

OH

Reduction

Oxidation

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ProgestinsProgestins

• Types1) C19- derived from testosterone

2) C21- derived from progesterone

• Role– in adequate doses it inhibits ovulation– Makes your body think that it is pregnant– Reduces levels of FSH and LH

• Binding– Interacts with progesterone receptors either

by entering cells through phospholipid bilayer or by interacting with surface proteins

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Structure of Structure of ProgestinsProgestins

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Brands of Oral Brands of Oral ContraceptivesContraceptives

• Alesse• Brevicon• Cyclessa• Demulen • Desogen • Estrostep • Genora• Intercon• Jenest • Levlen • Levlite• Levora

• Loestrin• Lo/Ovral• Mircette• ModiCo • Necon • N.E.E. • Nelova• Nordette • Norethin• Norinyl• Ortho-Cept • Ortho-Cyclen

• Ortho-Novum • Ortho Tri-Cyclen• Ovcon• Ovral• Tri-Levlen• Tri-Noriny • Triphasil • Trivora• Zovia

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Side Effects of Oral Side Effects of Oral ContraceptivesContraceptives

• Changes in:– Weight– Sexual desire– Vaginal discharge– Menstrual flow– Breast size– Blood pressure– complexion

• Other Common side effects:– Breakthrough bleeding– Nausea headaches– Urinary tract infection– Depression– Gum inflammation

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AbortifacientsAbortifacients

• An antagonist of progesterone can interfere with the early stages of pregnancy

MifepristroneRU 38,486 or RU 486

O

OH

H

N

CH3

H3C

C CCH3

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Future of Oral Future of Oral ContraceptivesContraceptives

• Researchers continually trying to minimize adverse side effects of oral contraceptives

• Pharmaceutical companies have to compete with latest forms of contraception– Contraceptive vaccines

– Vaginal rings

– Intrauterine Contraception

– Cervical caps

– Transdermal patch

– Implants and injectables

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ReferencesReferences• http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a601

050.html• http://en.wikipedia.org/wiki/Estrogen• http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/S/Sex

Hormones.html• http://www.emc.maricopa.edu/faculty/farabee/biobk/

BioBookREPROD.html• http://en.wikipedia.org/wiki/Gonadotropin_releasing_hormone• http://www.contraceptiononline.org/slides/slide01.cfm?

q=progestin+chemical+structures&dpg=1• http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/H/

Hormones.html• http://www.contraceptiononline.org/contrareport/

article01.cfm?art=93• http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/G/

G_Proteins.html