1. Steroids: Estrogens, Synthetic Estrogens, Estrogen Antagonists, Progestins, Synthetic Progestins
CHEM-5398
April 1, 2010

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

3. 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

4. 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

5. Mechanism (ctd)
- Hormone binding activates receptor protein and now both can bind specific regions of DNA called HRE
(Hormone Response Elements)

7. Video

8. Ovarian and Menstrual
cycles
and the
contraceptives
link

9. 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

10. 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

11. Estrogens Fun fact: Estrus = fertile, gen = to generate in Latin
Three major types of natural estrogens
Estrone (E1)
Estradiol (E2)
Most common!
Estriol (E3)

12. Estrogens
From menarche to menopause the primary estrogen is 17β-estradiol
Estradiol is produced from testosterone

14. 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.

15. 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.

16. Menopause
Transition period in a woman's life when her ovaries stop producing eggs, her body produces less estrogen and progesterone, and menstruation becomes less frequent
Symptoms are mood swings, hot flashes and vaginal dryness

17. Synthetic Estrogens
Can by synthesized from plants or biological organisms like horses
Examples include Synthroid or Quinestrol
Synthroid
Quinestrol

18. 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

19. 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

20. 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)

21. Progesterone/Progestins
Progesterone (pregn-4-ene-3,20-dione)

22. 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

23. Progesterone
Involved in female menstrual cycle, supports pregnancy, and embryogenesis in the womb
Synthesis:
Cholesterol
Pregnenolone
Progesterone

24. Progestins
Most frequent uses: Contraception and endometrial hyperplasia
Enovid/Norethynodrel: contraceptive

25. 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

26. 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

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

28. Combination HRTs
Pills:
Prempro
Patches:
CombiPatch

29. Patches vs. Pills
Different routes of administration = different side effects
Pills 2x likely to cause blood clots than patches

30. Estrogen HRTs Pills: Estrace Patches: Vivelle-dot Cream*: Dienestrol
Dangers of Estrogen Video
Dienestrol

31. Progestin HRTs Pills: Prometrium IUDs: Mirena (levonorgestrel)
Lasts up to 5 years

32. Negative effects of HRT

33. 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

34. Future research…
How testosterone and estrogen work together to control male dimorphic behaviors in rats (UCSF)
Alzheimer’s Disease and estrogen after menopause

35. Assigned Reading:
Goodman and Gilman’s Pharmacological Basis of Therapeutics pp. 1541and Large Print Only

36. 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.

37. 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),   
Simmons, Horst Ernest.  The Side Effects of  Estrogen   Drug  Therapy:  Contraception and Postmenopause.    (1979),     92 pp.