ROCK PINCUS 1960 CHANG E and P

1. ROCK PINCUS 1960 CHANG E and P

3. 10 year on Pill reduces ovarian cancer by 70%, endometrial cancer by 60%

4. Why do Japanese women have less breast cancer 3 Factors Explain Gap 1st period, weight, and E levels Hormone levels can influence Cancer. They are almost always have growth factor properties. Steriod receptors present in every cell type

5. TODAY… • the highest rates of new AIDS diagnoses are in • Miami (33.1 per 100,000 people) • 2. New Orleans (31.5) • 3. Baton Rouge (31.4) • 4. Washington DC (30.5).

6. RU-486

7. 2002 July 10th (WHI) clinical trial tracked the long term effects of hormone (HT) trial was being halted three years ahead of schedule. The results showed an unacceptable proportion of women were harmed by the therapy. Data implied that HT did not protect against memory loss and other neurodegenerative conditions such as dementia, and in fact increased their risk of stroke and breast cancer.

8. At the time, some 14 million US women were taking HT to relieve postmenopausal symptoms or to lower their risk for osteoporosis. Numerous studies had suggested that hormone treatment, using synthetic estrogens or a combination of synthetic estrogens and progestins, protected women from many diseases, whereas the absence of estrogen made women more vulnerable.

9. WHI -20,000 participants, was the largest clinical trial to date. With numbers like that it was very difficult to argue that estrogen wasn’t harmful. Was cause to argue estradiol, was protective against damage caused by stroke. Would estradiol influence the extent of injury in rats after we experimentally induced cerebrovascular stroke by blocking blood flow to a major vessel in the brain.

10. Animals with very low levels of estradiol experienced approximately half the amount of injury compared to animals without estrogens. Estradiol had to be present before we performed the stroke injury; otherwise treatment was totally ineffective in protecting the brain. Low doses were as effective as higher doses. Experiment was performed in mice, direct opposition to the WHI findings.

11. Estrogens - pleiotropic hormone which actd on a plethora of physiological functions not directly related to reproduction, therefore also important in male physiology. Estrogens were important players in the immune system, in cardiovascular function, in bone formation and breakdown, in fat distribution and metabolism, learning and memory.

12. Community of estrogen researchers rallied together Why the discrepancies between this major clinical trial and previous studies. Estrogens influenced many genes that regulate cell survival and cell death. Low concentrations of estradiol protected the brain by suppressing apoptosis.

13. Estradiol could change the expression of multiple genes and proteins. Estradiol helps maintain levels of bcl-2, a protein which reduces apoptosis after stroke. Estradiol inhibits caspases, proteins that mediate cell death. Stroke increased the expression of estrogen receptors to allow estrogen to protect the brain and enhance its repair. All of these changes tip the balance toward cell survival and against cell death.

14. WHI study had traced women before stroke had occurred to capture their risk, but didn’t follow women after their stroke to see if women taking estrogen had improved recoveries as models suggested. Men also produce estrogen and are protected after stroke when estrogens are present. Not possible to treat men with estrogen because the hormone has feminizing effects that are not acceptable. Development of compounds that use the same protective mechanisms, but do not have the other effects of estrogen.

15. Cytosolic estrogen receptor discovered in the 1960’s act by transporting estrogens attached to the receptor to the nucleus where the hormone-receptor complex bound to DNA and acted as a transcription factor. 30 years estrogens were thought to act: via a single receptor that acted by binding to the promoter region

16. In 1996 actually two different estrogen receptor subtypes: ERa and ERb ERa- or ERb-knock out mice and found that ERa plays a pivotal role in protecting the brain against cell death. ERb proved not to play a role in protection.

17. Develop drugs that target a specific receptor to allow better outcomes from stroke. Studies mean in terms of the results of the WHI? Two aspects of the clinical study design are worth considering. First, only synthetic hormones were used. Might account for differential actions of these substances compared to endogenous hormones.

18. Second, the average age of women when they started the WHI trial was 63 years old and most of them had not had hormone therapy previous to the trial. Most of them had been estrogen deficient for about 12 years.

19. Investigate what delayed the time of hormone treatment in mice to match that of the WHI. Did not treat mice immediately after ‘menopause,’ but waited for several weeks (the equivalent of several human years), that hormone treatment was totally ineffective.

20. Estradiol acts is by suppressing inflammation, thereby preventing cell death. Waited a few weeks unable to suppress inflammation. Depends upon the presence of ERa The timing or treatment is a critical factor to consider.

21. Different kinds of estrogens and different concentrations of hormone have different effects. Hormonal milieu makes a big different in how estrogens act Completely opposite effects depending upon what other hormones are present and whether they have been there before or after estrogen exposure.

22. Neurogenesis dogma had been that all neurons were born during embryonic and early postnatal development New neurons were born even in adulthood. Estrogen was important in the developing brain of an embryo. Fetal and early postnatal brain, estrogens are factors that mediate Neurogenesis, synapse formation and glial differentiation

23. Estrogens are potent neurogenic factors after stroke injury in the adult brain. Effect depends on both ERa and ERb. Uncertain how estradiol works to enhance Neurogenesis. Promise for the use of estrogens in the long-term repair and recovery of brain function

24. Clinical trials such as the WHI are impressive for the number of women they study. But because of prohibitive costs of performing such a large clinical trial, only a limited number of questions can be addressed. In the year following WHI trail 40% of women stopped taking hormone replacement therapy

25. Realized that results should have been interpreted with more caution. Functions depend upon dose, preparation, method of administration, the recipient’s age, genetics and previous exposure to the hormone.

26. Estrogens should be expected to be among the most complex ones to understand: they exhibit a diurnal rhythm, a monthly rhythm that is determined by the menstrual cycle, and they act differently depending upon whether other reproductive hormones are present in high or low concentrations. Estrogens are not the panacea people thought they were, but neither are they always harmful.

27. July 10-2002 WHI clinical trial tracked the long term effects of hormone (HT) trial was being halted 3 years ahead of schedule. Results showed an unacceptable proportion of women were harmed by the therapy. Data implied that HT did not protect against memory loss and other neurodegenerative conditions such as dementia, and in fact increased their risk of stroke and breast cancer.

28. At the time, some 14 million US women were taking HT to relieve postmenopausal symptoms or to lower their risk for osteoporosis. Numerous studies had suggested that hormone treatment, using synthetic estrogens or a combination of synthetic estrogens and progestins, protected women from many diseases, whereas the absence of estrogen made women more vulnerable.

29. WHI-20,000 participants-was the largest clinical trial to date. #s like that it was very difficult to argue that estrogen wasn’t harmful. Was cause to argue estradiol, was protective against damage caused by stroke. Would estradiol influence the extent of injury in rats after we experimentally induced cerebrovascular stroke by blocking blood flow to a major vessel in the brain.

30. Animals with very low levels of estradiol experienced approximately half the amount of injury compared to animals without estrogens. Estradiol had to be present before we performed the stroke injury; otherwise treatment was totally ineffective in protecting the brain. Low doses were as effective as higher doses. Experiment was performed in mice, direct opposition to the WHI findings.

31. Estrogens - pleiotropic hormone which act on a plethora of physiological functions not directly related to reproduction, therefore also important in male physiology. Estrogens were important players in the immune system, in cardiovascular function, in bone formation and breakdown, in fat distribution and metabolism, learning and memory.

32. Community of estrogen researchers rallied together Why the discrepancies between this major clinical trial and previous studies. Estrogens influenced many genes that regulate cell survival and cell death. Low concentrations of estradiol protected the brain by suppressing apoptosis.

33. Estradiol could change the expression of multiple genes and proteins. Estradiol helps maintain levels of bcl-2, a protein which reduces apoptosis after stroke. Estradiol inhibits caspases, proteins that mediate cell death. Stroke increased the expression of ERs to allow estrogen to protect the brain and enhance its repair. All of these changes tip the balance toward cell survival and against cell death.

34. WHI study had traced women before stroke had occurred to capture their risk, but didn’t follow women after their stroke to see if women taking estrogen had improved recoveries as models suggested. Men also produce estrogen and are protected after stroke when estrogens are present. Not possible to treat men with E because the hormone has feminizing effects that are not acceptable. Development of compounds that use the same protective mechanisms, but do not have the other effects of estrogen.

35. Cytosolic estrogen receptor discovered in the 1960’s act by transporting estrogens attached to the receptor to the nucleus where the hormone-receptor complex bound to DNA and acted as a transcription factor. 30 years estrogens were thought to act: via a single receptor that acted by binding to the promoter region

36. In 1996 actually two different estrogen receptor subtypes: ERa and ERb ERa or ERb-knock out mice and found that ERa plays a pivotal role in protecting the brain against cell death. ERb proved not to play a role in protection.

37. Develop drugs that target a specific receptor to allow better outcomes from stroke. Studies mean in terms of the results of the WHI? Two aspects of the clinical study design are worth considering. First, only synthetic hormones were used. Might account for differential actions of these substances compared to endogenous hormones.

38. Second- the average age of women when they started the WHI trial was 63 years old and most of them had not had HT previous to the trial. Most of them had been estrogen deficient for about 12 years.

39. Investigate what delayed the time of hormone treatment in mice to match that of the WHI. Did not treat mice immediately after ‘menopause,’ but waited for several weeks (the equivalent of several human years), that hormone treatment was totally ineffective.

40. Estradiol acts is by suppressing inflammation, thereby preventing cell death. Waited a few weeks unable to suppress inflammation. Depends upon the presence of ERa The timing of treatment is a critical factor to consider.

41. Different kinds of estrogens and different concentrations of hormone have different effects. Hormonal milieu makes a big different in how estrogens act Completely opposite effects depending upon what other hormones are present and whether they have been there before or after estrogen exposure.

42. Neurogenesis dogma had been that all neurons arise during embryonic and early postnatal development Now known that new neurons can occur even in adulthood.

43. Estrogen - important in the developing brain of an embryo. Fetal and early postnatal brain, estrogens - mediate neurogenesis, synapse formation and glial differentiation

44. Estrogens are potent neurogenic factors after stroke injury in the adult brain. Effect depends on both ERa and ERb. Uncertain how estradiol works to enhance Neurogenesis. Promise for the use of estrogens in the long-term repair and recovery of brain function

45. Clinical trials such as the WHI are impressive for the # of women they study. But because of prohibitive costs of performing such a large clinical trial, only a limited # of questions can be addressed. In the year following WHI trail 40% of women stopped taking HRT

46. Realized that results should have been interpreted with more caution. Functions depend upon dose, preparation, method of administration, the recipient’s age, genetics and previous exposure to the hormone.

47. Estrogens should be expected to be among the most complex hormones to understand: they exhibit a diurnal rhythm, a monthly rhythm that is determined by the menstrual cycle, and they act differently depending upon whether other reproductive hormones are present in high or low concentrations. Estrogens are not the panacea people thought they were, but neither are they always harmful.

48. genetic sex established at conception Direction of differentiation due to hormones Gonadal sex regulates the phenotypic sex Dev’t of brain dependent on hormones present Compared to female, male dev’t of reproductive system is uncomplicated. After puberty-male is tonic Female is cyclic in hormonal output and gonadal function Also she can become pregnant Unique female hormones Milk production after delivery

49. Genetic Sex, determine at conception governs the development of the gonadal sex of the individual Gonadal sex regulates development of phenotypic sex Differentiation of internal and external sex organs as well as attainment of adult sexual characteristics.

50. Chromosomal (genetic) basis of sex determination No matter what chromosome #is-lack of Y-get a female Although the genetic sex of the species determine the direction in which the gonads initially differentiate, the exogenous administration of sex steroids at a critical time (varies among species) can induce permanent gonadal sex reversal