CHEM-5398 April 1, 2010. Background: Steroids overview, etc History Estrogen Synthetic Estrogens...
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Transcript of CHEM-5398 April 1, 2010. Background: Steroids overview, etc History Estrogen Synthetic Estrogens...
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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
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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.