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 Hormone Replacement Therapy (HRT) Future Research…

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 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

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

Video

Ovarian and Menstrual cycles and the contraceptives link

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 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

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

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

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.

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 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

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

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

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

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

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) 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 Combination: - Pills and patch Estrogen: - Pills, patch, cream Progestins - Pills, vaginal gels, IUDs

Combination HRTs Pills: Prempro Patches: CombiPatch

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

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

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

Negative effects of HRT

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

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

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 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.