ROCK

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ROCK PINCUS 1960 CHANG E and P
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(No Transcript)
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
wasnt 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 didnt 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
1960s 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 recipients 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 wasnt
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 didnt 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
1960s 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 recipients 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 Devt of brain
dependent on hormones present Compared to
female, male devt 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

51
Sex Chromosomes and Determination of Sex Humans
usually have 46 chromosomes per diploid cell
consisting of 22 sets of autosomes and a set of
sex chromosomes - either XX or XY. In the usual
course of events, individuals with the karyotype
46, XX are female and individuals with 46, XY,
are male. How is the sex of an individual is
determined. Is sex determined by the number of X
chromosomes - with one X you are male or with 2
X's you are female? Or is sex determined by the
presence or absence of the Y chromosome - the
presence of a Y makes for a male or the absence
of a Y produces a female?

52
Sex Chromosomes and Determination of Sex One way
the answer was provided by individuals resulting
from non-disjunction of the sex chromosomes. Some
individuals have 45 chromosomes and have only one
X chromosome other individuals have 47
chromosomes and have two X chromosomes and a Y.
The table below indicates the sex of these
individuals. ChromosomeConstitution Name of
Syndrome Sex Frequency in Population 46,
XX
NormalFemale 0.511 46, XY

NormalMale 0.48945, XO
Turner's Syndrome Female
1/5,00047 XXY Klinefelter's
Syndrome Male
1/700Female (46,XX) and Male (46,XY)
frequencies taken from the US Census projection
of July 1, 1996 with no correction for chromosome
constitution. It is clear that the presence of a
Y chromosome is necessary for male sexual
characteristics to develop. The number of X
chromosomes present does not play a significant
role in sex determination.

53
SRY Sex determination We have come a long way
in our understanding of sexual dimorphism since
355 BC. Aristotle suggested that the difference
between the two sexes was due to the heat of
semen at the time of copulation hot semen
generated males, whereas cold semen made females.
Thankfully, we now know a little more about the
molecular events of sex determination. Usually,
a woman has two X chromosomes (XX) and a man one
X and one Y (XY). However, both male and female
characteristics can sometimes be found in one
individual, and it is possible to have XY women
and XX men. Analysis of such individuals has
revealed some of the molecules involved in sex
determination, including one called SRY, which is
important for testis formation.

54
SRY Sex determination SRY (which stands for
sex-determining region Y gene) is found on the Y
chromosome. In the cell, it binds to other DNA
and in doing so distorts it dramatically out of
shape. This alters the properties of the DNA and
alters the expression of a number of genes,
leading to testis formation. Most XX men who lack
a Y chromosome do still have a copy of the SRY
region on one of their X chromosomes. This copy
accounts for their maleness. However, because the
remainder of the Y chromosome is missing they
frequently do not develop secondary sexual
characteristics in the usual way. Since human
SRY is similar to SRY of mice, a model of SRY
function has been developed in mice. This has
been particularly important in discovering the
interactions of SRY with other genes in male sex
determination.

55
Mammalian testicular organogenesis dependent on
protein SRY (TDF) Female mice embryos with
normal pair of XX - injected with a small piece
of Y containing SRY, they grow up as males with
testis and male behavior Y triggers the genital
ridges in embryo to develop into testes rather
than ovaries Once that happens, all other changes
that make a male follow under the influence of
hormones produced by the testes SRY gene is only
a SWITCH

56

SRY is only a switch because testes can develop
in XX women who have no portion of the Y In
cattle, some genetic females have testes So,
genes found in females
57

Gonadal Steroid and Brain Differentiation Expts
have shown that transplantation of the pit from a
male to a female rat to the opposite sex did not
alter the normal reproductive processes in either
sex. Pits are equivalent We know tonic in males
and cyclic in females
58

Neonatal male develop into adult make with male
behavior But if castrate at critical period
becomes a feminized male with female
behavior Neonate female develops into adult
female with female behavior But if put in
testosterone at critical period then get
masuclinized female with male behavior
59

These results suggest that control of pit hormone
secretion and subsequent gonadal function depend
on a system that is programmed early in
development was not localized to the pit or the
gonads.
60
Steroid hormones derived from Cholesterol Andros
tenedione (testis) Testosterone
Estradiol
5a reductase
DHT

61
A single treatment of a chick embryos with an
aromatase inhibitor at a stage when gonads are
bipotential causes genetic females to
permanently develop a male phenotype
Aromatase is key developmental switch in the
sex determination of chickens

62
Many breast tumors are highly "estrogen
sensitive," so estrogen stimulates their
growth. Aromatase inhibitors (AIs) can help block
the growth of these tumors by lowering the amount
of E in the body. Estrogen is produced by the
ovaires and other tissues of the body, via
aromatase. AIs do not block estrogen production
by the ovaries, but they can block other tissues
from making this hormone. That's why AIs are used
mostly in women who have reached menopause, when
the ovaries are no longer producing
estrogen. Currently severa AIs approved by the
U.S. Food and Drug Administration anastrazole
(Arimidex), exemestane (Aromasin), and
letrozole (Femara).