Let's move on to anti-estrogenic agents.
Let's start off with SERMs.
What is a SERM?
A SERM stands for selective estrogen receptor modulator.
Now, the classic and prototypical drug
that you really need to know well is tamoxifen.
Tamoxifen is used as an ER agonist –
pardon me, antagonist in breast tissue.
It reduces the risk of breast cancer
in those patients that are ER positive.
Now, ER agonists in endometrial tissue
promote endometrial hyperplasia
and increase the risk of endometrial cancer.
What are the side effects of tamoxifen?
As an agonist,
you can get hot flashes and prevent osteoporosis.
As an antagonist,
you increase the risk of venous thromboembolism.
The next of the SERMs
that are important to know is raloxifene.
Now, raloxifene is used
in a slightly different therapeutic area.
It is approved for the prevention
and treatment of osteoporosis.
It has antagonistic effects that include
reducing the risk of breast cancer,
but its agonistic effects –
there is no estrogenic effects on endometrial tissue,
which is unlike tamoxifen.
Now, the big issue here is,
is that because it's working peripherally,
but not on endometrial tissue,
this is why we find that it's a particularly useful drug
for treating diseases like osteoporosis.
Other agents are used for menopausal symptoms as well
and osteoporosis prevention
alongside of estrogens.
Clomiphene reduces negative feedback in pituitary tissue,
so that increases LH and FSH secretion.
This is an ovulation inducer in patients who are anovulatory.
Let's move on to the full antagonists.
Fulvestrant is a pure estrogen antagonist in all tissues.
So, it is unlike the SERMs,
in that it has antagonistic actions everywhere.
The SERMs have agonistic actions in some tissues
and antagonistic in others.
It is used in breast cancer with resistance to tamoxifen.
And it is used in women with breast cancer
with endometrial risk factors.
Another set of anti-estrogens are the aromatase inhibitors.
Anastrozole and letrozole are
non-steroidal competitive aromatase inhibitors.
They are used also in the treatment of breast cancer.
Irreversible aromatase inhibitors are also used
in the treatment of breast cancer.
They act by blocking the estrogen activity in breast tissue.
Danazol is an agent that inhibits Cytochrome P450 enzymes
involved in gonadotropin synthesis.
It is a weak partial agonist of progestin,
and, to some extent, estrogen receptors as well.
It is used in the treatment of endometriosis
and fibrocystic disease of the breast.
Let's move on to other agents involved in anti-estrogen activity.
Leuprolide was discussed in a previous lecture.
I’ll just quickly say
Leuprolide was discussed in a previous lecture.
that it is involved in continuous stimulation of
the gonadotrophic releasing hormone receptors in the hypothalamus.
Now, why would it happen that continuous excitation
of the GnRH receptors will cause suppressed secretion
and an intermittent stimulation of GnRH will cause increased secretion.
That's a difficult concept to understand,
but if you think back to our original pharmacology lectures,
it has to do with down-regulation/up-regulation of receptors.
So, continuous stimulation of GnHR receptors
are going to cause a suppressed secretion.
So, just remember that.
Now, this ends up inhibiting ovarian production
of estrogen and progesterone,
and that's how it gives its anti-estrogen activity.
Now, in terms of how we use this medication,
we use it in the treatment of precocious puberty.
In short-term treatment,
it is also used in the treatment of endometriosis.
And in short-term treatment,
it can also be used for fibroids.
There are other agents that are used to control
ovarian hyperstimulation syndrome.
All of these agents end in -elix
and we sometime call them the elixir drugs.
Abarelix and degarelix are used in prostate cancer in men.
This is used usually in the
first week of therapy alongside leuprolide.
It is less likely to cause a tumor flare with this combination.
So, remember that these are hormonally active agents
that can be useful in both men and women.
Let's move on to the anti-progestin agents.
Mifepristone is the prototypical anti-progestin.
You may remember it as RU 486
because it was extremely controversial
when it was first released on to the market.
It is a direct antagonist of progesterone receptors.
It is also an antagonist of glucocorticoid receptors.
It was first brought in as an abortifacient
up to 49 days after the last menstrual period.
And for that reason,
it was an exceedingly controversial pill.
It is also used in combination
with other agents like misoprostol
to end up giving you a 95% termination rate.
Side effects of this medication include nausea,
vomiting and diarrhea,
cramping and bleeding.
we see an increase in unusual infections
in association with using this medication.
We’re not really sure why
these particular agents
are more likely to infect patients
who take this medication.