00:01
I'm Dr. Shukle.
00:02
We're going to cover
a topic called
Selective Estrogen Receptor
Modulators.
00:07
This is a difficult concept
for a lot of medical students.
00:10
So, we're going to take our time
going over it,
and try and get the understanding
really up to a high level.
00:18
When we take a look at the overall
armamentarium that we use in
Gonadal hormone agonists
and antagonists,
you can see that the SERMs
or Selective Estrogen
Receptor Modulators
fall under the
receptor antagonists.
00:32
Why is that?
Well, because from a
pharmacological point of view,
this is what we're using it for.
00:38
We're using it for
its antagonistic action,
not for its agonistic action.
00:44
Now have a look at this diagram.
It's a really nice diagram.
00:47
After this lecture is over,
I want you to pause the video
and study it
so that you can see
where all of the drugs fit in.
00:53
The first of these SERMs
that I want to talk about
is probably the most famous of them,
and it's used most commonly
in breast cancer,
and that is Tamoxifen.
01:02
Now, it acts as an
estrogen antagonist
in breast tissue,
and that's why we're using it.
01:09
So it reduces the risk of high risk
patient breast cancer,
and it also reduces the risk
that there's a recurrence
once we've finished
our treatment.
01:17
So a lot of times you'll see people
being put on Tamoxifen,
after they've had their
chemotherapy,
radiotherapy, and surgery
from breast cancer.
01:26
One of the disadvantages
of this particular drug
is that it does work as an
agonist in the endometrial tissue,
so that can promote
endometrial hyperplasia,
and it can increase the risk
of endometrial cancer.
01:40
So this is one of the great
disadvantages of this medication.
01:44
Now, there are other agents within
the drug class
that has have less agonistic
activity
and therefore have lower endometrial
risk factors.
01:56
Regarding its side effects
as an antagonist,
you increase the risk of hot flashes
and other menopausal symptoms.
02:02
As an agonist, Tamoxifen decreases
the risk of osteoporosis,
but there is an increased risk in
venous thromboembolism.
02:10
Raloxifene is a cousin of Tamoxifen.
02:14
It is also approved
for the prevention
of osteoporosis.
02:18
It is an antagonistic effect that
reduces breast cancer risk.
02:23
It's agonistic effect does not have
any significant estrogenic effects
on the endometrail tissue,
unlike Tamoxifen,
which makes it a little bit better
in terms of endometrial cancer risk.
02:35
So it's a very nice drug
that's come along
and starting to be picked up
more and more in terms of use.
02:44
Another drug in this drug classes
Bazedoxifene,
which is also a cousin of Tamoxifen.
02:49
You can see that these
agents all end in F-E-N-E
except for tamoxifen,
which the E was dropped
for some reason
that I can't explain.
03:00
But generally speaking,
when you have that suffix,
that's the class of drugs
we're talking about.
03:05
This also is used for
menopausal symptoms,
and it's also used for
osteoporosis prevention
with estrogens.
03:14
Clomiphene is another example
of a drug in this drug class.
03:17
It reduces the negative feedback
loop in the pituitary.
03:22
What you end up having
when you give this medication
is you have an increase
in the luteinizing hormone
and follicular stimulating hormone.
03:30
Why would we ever
want to do that?
Well in patients who don't have
ovulation or an ambulatory patients,
it actually can induce ovulation.
03:42
Now let's move on
to the full antagonists.
03:44
An example of the full antagonists
include drugs like Fulvestrant.
03:50
It is a pure estrogen antagonist
in all tissues,
whether you're talking about
breast or endometrium.
03:56
So it is used in breast cancer,
in patients who are resistant
to Tamoxifen.
04:02
And it is also used in patients
who have breast cancer
who also have high risk for
endometrial cancer.
04:09
So although it isn't used
as much as Tamoxifen,
it is a very good drug.
04:13
And you can see where it fits
on our pathway here
it's right next to
the Tamoxifens.
04:20
The next category of our drugs
are the aromatase inhibitors.
04:23
They're also called
synthesis inhibitors.
04:26
Why do we call them
synthesis inhibitors?
Because if you take a look
at our diagram here,
you'll see that aromatase
is really responsible
for the one of the last steps
in the production of estrogen.
04:38
Now, these drugs are nonsteroidal
competitive aromatase inhibitors.
04:44
They are used
in the treatment of breast cancer
for obvious reasons
because we want to reduce
the effects of estrogen
on the breast cancer.
04:51
Another agent in this class is
Exemestane.
04:55
which is an irreversible
aromatase inhibitor.
04:59
Now, I put it in a slightly
different category
because it is irreversible.
05:03
It is also used in the treatment of
breast cancer.
05:07
Let's move on to other drug classes specifically
the gonadotropin releasing hormone agonists and antagonists, as well as danazol.
05:15
Now, this is a complicated drug.
05:17
And I'll tell you why.
05:19
Danazol is the prototypical drug
in this drug class,
there are others,
but let's focus on Danazol.
05:24
Now this drug or this agent
inhibits more than
45 different enzymes
that are involved in not just
gonadotropin synthesis,
but other types of
complex molecule synthesis as well.
05:36
So it's a very complicated drug.
05:37
It is metabolized by
cytochrome p450
and you should be aware
that it can have drug interactions.
05:45
It is a weak partial agonist
of progestin,
androgen,
and glucocorticoid receptors.
05:52
So it's a complex set of
effects here.
05:55
It is used in the treatment
of endometriosis.
05:59
It is used in the treatment of
fibrocystic disease of the breast,
and it can be used in other
dysmorphic diseases
of the endometrium.
06:09
I'm going to move on to a slightly
different category of drugs.
06:12
These are the
gonadotropin-releasing hormone
analogues,
which means that they simulate
the activity of
gonadotropin releasing hormone.
06:21
The first of this that I'm going to
talk about is Leuprolide.
06:25
Now, we have discussed this
in a previous lecture,
but I'll just mention it here
for completeness sake.
06:33
This provides continuous stimulation
of GnRH receptors,
which actually end up suppressing
secretion in the long run.
06:40
Why does that happen?
Well think about teasing
your little brother
or your little sister,
continuous teasing
of your
little brother or little sister
eventually results in
that sibling ignoring you.
06:52
It's kind of the same thing
with the brain and with the body.
06:55
If you have continuous stimulation
of certain types of receptors,
eventually,
the effect of that stimulation
becomes less and less.
07:05
That happens through
a process called
Receptor-mediated endocytosis,
also called downregulation.
07:11
So you end up taking in
those receptors
And you destroy them
at a higher rate
than you're producing them.
07:15
Eventually, you have fewer receptors
to respond to your stimulus
and you have less of an effect.
07:22
Now, the end result
of using a drug like this
is that it inhibits
ovarian production
of estrogen and progesterone.
07:28
So it is an anti estrogen
and anti progesterone medication.
07:34
We use this in the treatment
of precocious puberty in girls.
07:37
So if patients have high levels
of estrogen and progesterone
at a very young age,
and they start to have
early puberty,
we can use this agent
to delay puberty.
07:49
We also use this short term
for the treatment of endometriosis.
07:52
We don't want to use it long term
for obvious reasons.
07:55
And we can use it
short term
for the treatment of fibroids
as well,
which is kind of the same process
as the endometriosis.
08:03
Let's move on now to the
Gonadotropin-releasing
hormone antagonists.
08:09
So Ganirelix is one of the
first examples that we'll use.
08:12
And sometimes this is used for
controlled ovarian hyperstimulation
in patients
who are anovulatory.
08:18
We can also use certain agents
in prostate cancer in men,
because again, you're antagonizing
the effects of
gonadotropin releasing hormone
so it can be used in males.
08:29
Now, we can use it in females
as well.
08:32
It is used in the first week
of therapy with leuprolide
in those patients.
08:37
We are less likely
to cause a tumor flare
with this combination.
08:41
The next category of drugs
are the antiprogestins.
08:44
And the most famous of these
is Mifepristone,
which is also known as RU 486.
08:49
So you may remember this
as being very controversial
when it was first released
onto the market.
08:54
It is an antagonist of progesterone
and it is also an antagonist
of glucocorticoids.
09:01
The use was for as an
Abortifacient
and it is also given in combination
with misoprostol
- with a 95% termination rate.
09:11
Side effects of this
particular agent include
nausea, vomiting, and diarrhea.
09:17
You can also get
cramping and bleeding.
09:19
And you may have episodes
of unusual infections
like Clostridium
for some unknown reason,
and we can't really explain
why that happens.
09:27
Okay, that's great.
09:29
We covered a couple of these
medications.
09:32
Go to your exam, feel confident, and
show them what you know.