Steroids estrogens synthetic estrogens estrogen antagonists progestins synthetic progestins
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Steroids: Estrogens, Synthetic Estrogens, Estrogen Antagonists, Progestins , Synthetic Progestins. CHEM-5398 April 1, 2010. Outline. Background: Steroids overview, etc History Estrogen Synthetic Estrogens Estrogen Antagonists/SERMs Progesterone Synthetic Progestins

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Steroids estrogens synthetic estrogens estrogen antagonists progestins synthetic progestins

Steroids: Estrogens, Synthetic Estrogens, Estrogen Antagonists, Progestins, Synthetic Progestins

CHEM-5398

April 1, 2010


Outline

Outline

  • Background: Steroids overview, etc

  • History

  • Estrogen

  • Synthetic Estrogens

  • Estrogen Antagonists/SERMs

  • Progesterone

  • Synthetic Progestins

  • Hormone Replacement Therapy (HRT)

  • Future Research…


Steroids basics

Steroids basics

  • 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


Steroid basics

Steroid basics

  • 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


Chem 5398 april 1 2010

  • Mechanism (ctd)

    - Hormone binding activates receptor protein and now both can bind specific regions of DNA called HRE

    (Hormone Response Elements)


Chem 5398 april 1 2010

Video


Chem 5398 april 1 2010

Ovarian andMenstrual

cycles

and the

contraceptives

link


History

History

  • 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


Estrogens

Estrogens

  • 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


Estrogens1

Estrogens

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

  • Three major types of natural estrogens

Estrone (E1)

Estradiol (E2)

Most common!

Estriol (E3)


Estrogens2

Estrogens

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

  • Estradiol is produced from testosterone


Estrogen receptors

Estrogen Receptors

  • 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.


Chem 5398 april 1 2010

  • 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.


Menopause

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


Synthetic estrogens

Synthetic Estrogens

  • Can by synthesized from plants or biological organisms like horses

  • Examples include Synthroid or Quinestrol

Synthroid

Quinestrol


Estrogen antagonists serms

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


Serms

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


Uses of serms

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)


Progesterone progestins

Progesterone/Progestins

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


History1

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


Progesterone

Progesterone

Involved in female menstrual cycle, supports pregnancy, and embryogenesis in the womb

Synthesis:

Progesterone

Cholesterol

Pregnenolone


Progestins

Progestins

Most frequent uses: Contraception and endometrial hyperplasia

Enovid/Norethynodrel: contraceptive


Progestin antagonists

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


Hormone replacement therapy hrt

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


Modes of hrt

Modes of HRT

Combination:

- Pills and patch

Estrogen:

- Pills, patch, cream

Progestins

- Pills, vaginal gels,

IUDs


Combination hrts

Combination HRTs

Pills:

Prempro

Patches:

CombiPatch


Patches vs pills

Patches vs. Pills

Different routes of administration = different side effects

Pills 2x likely to cause blood clots than patches


Estrogen hrts

Estrogen HRTs

Pills: Estrace

Patches: Vivelle-dot

Cream*: Dienestrol

Dangers of Estrogen Video

Dienestrol


Progestin hrts

Progestin HRTs

Pills:Prometrium

IUDs:

Mirena (levonorgestrel)

Lasts up to 5 years


Negative effects of hrt

Negative effects of HRT


Mayo clinic research on hrt risks

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


Future research

Future research…

How testosterone and estrogen work together to control male dimorphic behaviors in rats (UCSF)

Alzheimer’s Disease and estrogen after menopause


Assigned reading

Assigned Reading:

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


Chem 5398 april 1 2010

  • Homework Questions:

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

  • What 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.


Sources

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. 


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