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Page 1: [PPT]Steroids: Estrogens, Synthetic Estrogens, Estrogen ...faculty.smu.edu/jbuynak/Steroids Presentation1.ppt · Web viewTitle Steroids: Estrogens, Synthetic Estrogens, Estrogen Antagonists,

CHEM-5398

April 1, 2010

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Background: Steroids overview, etc History Estrogen Synthetic Estrogens Estrogen Antagonists/SERMs Progesterone Synthetic Progestins Hormone Replacement Therapy (HRT) Future Research…

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Steroid hormones are all derived from cholesterol

Cholesterol contains cyclopentanophenanthrene ring

Estrogen and progestins are just two of the many steroids found in the human body

Cholesterol

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Mechanism: - Modulate gene expression inside cell - They are not water-soluble so travel

in blood attached to protein carriers - When they reach the cell, they

dissociate from protein carrier and enter membrane

- Some bind to a receptor in the cytoplasm and move in to the nucleus

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Mechanism (ctd) - Hormone binding activates receptor

protein and now both can bind specific regions of DNA called HRE

(Hormone Response Elements)

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Video

Page 8: [PPT]Steroids: Estrogens, Synthetic Estrogens, Estrogen ...faculty.smu.edu/jbuynak/Steroids Presentation1.ppt · Web viewTitle Steroids: Estrogens, Synthetic Estrogens, Estrogen Antagonists,

Ovarian andMenstrual

cycles and the contraceptives link

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1926: Loewe and Lange discovered that a female sex hormone varied throughout menstrual cycle.

1928: Zondek reported excretion of estrogen during pregnancy.

In 1929 Adolf Butenandt and Edward Adelbert Doisy independently isolated and determined the structure of estrogen.

The first orally effective estrogen, Emmenin, was derived from the late-pregnancy urine of Canadian women, and was introduced in 1930

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Function as the primary female sex hormones

Present in both men and women Promote development of female

secondary sex characteristics Stimulate endometrial and uterine

growth Reduce bone resorption, increase bone

formation

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Fun fact: Estrus = fertile, gen = to generate in Latin

Three major types of natural estrogens

Estrone (E1) Estradiol (E2)Most common!

Estriol (E3)

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From menarche to menopause the primary estrogen is 17β-estradiol

Estradiol is produced from testosterone

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Estrogens act as signaling molecules by interacting with specific target cells.› Include tissues of the breast, uterus, brain, heart, liver,

and bone.

These target cells have estrogen receptors. › There are two estrogen receptors that are normally

found in the cell’s nucleus: ER α and ER β.

The receptor undergoes dimerization in order for it to have increased affinity for DNA.

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This estrogen-receptor complex can now bind to specific DNA sites, called estrogen response elements (EREs).

Genes are activated to produce messenger RNA, which guide the synthesis of new proteins, determined by the cell type.

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Menopause Transition period in a woman's life when

her ovaries stop producing eggs, her body produces less estrogen andprogesterone, and menstruation becomes less frequent

Symptoms are mood swings, hot flashes and vaginal dryness

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Can by synthesized from plants or biological organisms like horses

Examples include Synthroid or Quinestrol

Synthroid Quinestrol

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Estrogen Antagonists/SERMs Estrogen antagonists are proteins that

block the actions of estrogen by binding to estrogen receptors

As a result, estrogen can not bind

Example: Evista/Raloxifene

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SERMs Selective Estrogen Receptor Modulators Because Estrogen receptors differ slightly

in different organs, SERMs can target receptors of a certain organ

So a SERM that blocks estrogen’s effects in breast cells won’t impact estrogen binding in the uterus!

Tamoxifen

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Uses of SERMs.. Used before or after menopause Can help in slowing metastasis of

cancer Can treat osteoporosis Advantage: specificity Yet to find a SERM that has no negative

side effect (delte this: both mentioned cause colon cancer)

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Progesterone/Progestins

Progesterone (pregn-4-ene-3,20-dione)

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History 1935: Progesterone is

discovered and named 1938: first orally active

progestin is synthesized in Germany

1950s: More viable oral progestin synthesized in Mexico City by Miramontes; approved in US

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Progesterone Involved in female menstrual cycle,

supports pregnancy, and embryogenesis in the womb

Synthesis:

Cholesterol Pregnenolone Progesterone

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Progestins Most frequent uses: Contraception and

endometrial hyperplasia

Enovid/Norethynodrel: contraceptive

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Progestin antagonists When these bind receptors, they produce a

delay in endometrial maturation and postpone the appearance of the implantation window

Therefore, used to terminate pregnancies

PRMs – Progesterone receptor modulators (contraceptives)

Mifepristone

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Hormone Replacement Therapy (HRT)

Estrogen + progestins or either! Medical treatment for menopausal or

post-menopausal women Progestins keep weight off and stop cell

proliferation Benefits of estrogen:

› Reduction in loss of bone mass (osteoporosis)› Decreased risk of cardiovascular disease› Positive effect on cognitive function

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Modes of HRT Combination: - Pills and patch Estrogen: - Pills, patch, cream Progestins - Pills, vaginal gels, IUDs

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Combination HRTs Pills: Prempro

Patches: CombiPatch

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Patches vs. Pills Different routes of administration =

different side effects Pills 2x likely to cause blood clots than

patches

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Estrogen HRTs Pills: Estrace

Patches: Vivelle-dot

Cream*: Dienestrol

DienestrolDangers of Estrogen Video

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Progestin HRTs Pills:

Prometrium

IUDs:Mirena (levonorgestrel)Lasts up to 5 years

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Negative effects of HRT

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Mayo Clinic Research on HRT risks In the largest clinical trial to date, the

combination estrogen-progestin (Prempro) increased the risk of certain serious conditions.

According to the study, over one year, 10,000 women taking estrogen plus progestin might experience:

- Seven more cases of heart disease than women taking a placebo

- Eight more cases of breast cancer than women taking a placebo

- Eight more cases of stroke than women taking a placebo

- Eighteen more cases of blood clots than women taking a placebo

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Future research… How testosterone and estrogen work

together to control male dimorphic behaviors in rats (UCSF)

Alzheimer’s Disease and estrogen after menopause

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Assigned Reading:

Goodman and Gilman’s Pharmacological Basis of Therapeutics pp. 1541and 1548-1568. Large Print Only

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Homework Questions:

1What is a SERM? What are SERMs used for? Draw the structure of tamoxifen.

2What is Combipatch and how is it used? Draw the structures of the two ingredients and list the general classes of molecules to which each of these two ingredients belongs.

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Sources The Pharmacological Basis of Therapeutics by

Goodman and Gilman “Progesterone vs Progestin” by Dr. Steven Hotze “Perspective: Female Steroid Hormone Action” by Dr.

Orla Conneely General, Sascha; Terebesi, Ildiko; Bracht, Stefan;

Funke, Adrian.  Progestin -containing drug delivery system.    PCT Int. Appl.  (2010),     77pp. 

Daniels, Rolf.  Estrogen   drug  delivery systems.    Pharmazie in Unserer Zeit  (2004),  33(5),  392-397. 

Simmons, Horst Ernest.  The Side Effects of  Estrogen   Drug  Therapy:  Contraception and Postmenopause.    (1979),     92 pp.