Anti-Estrogens and Antiprogestins – Reproductive Pharmacology

by Pravin Shukle, MD

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    00:02 I’m Dr. Shukle. We’re going to cover a topic called selective estrogen receptor modulators.

    00:07 This is a difficult concept for a lot of medical student so weâ€(Trademark)re going to take out 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 agonist and antagonist, you can see that the SERMs or selective estrogen receptor modulators fall under the receptor antagonist.

    00:32 Why is that? Well, because from a pharmacological point of view this is what weâ€(Trademark)re using it for.

    00:38 Weâ€(Trademark)re using it for its antagonistic action not for its agonistic action.

    00:44 Now have a look at this diagram, itâ€(Trademark)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 the drugs fit in.

    00:54 The first of these SERMs that I want to talk about is probably the most famous of them and is used most commonly in breast cancer and that is tamoxifen.

    01:03 Now it acts as an estrogen antagonist in breast tissue and thatâ€(Trademark)s why weâ€(Trademark)re using it.

    01:09 So it reduces the risk of high risk patient in breast cancer and it also reduces the risk of that thereâ€(Trademark)s recurrence once we finished our treatment so a lot of times youâ€(Trademark)ll see people being put on tamoxifen after theyâ€(Trademark)ve had their chemotherapy, radio therapy 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 so this is one of the great disadvantages of this medication.

    01:45 Now there are other agents within the drug class that has have less agonistic activity and therefore have lower endometrial risk factors.

    01:56 Side effects of tamoxifen and its analogues include hot flashes in its antagonistic phase, as well as a prevention of osteoporosis which is kind of a side effect but kind of a benefit.

    02:09 In terms of its agonistic activity as I said before, it increases your risk of endometrial cancer in high risk patients but also it increases your risk of venous thrombosis which can be increased with high levels of estrogen so an agonistic activity increases the risk of venous thrombosis as well.

    02:29 Raloxifene is a cousin of tamoxifene.

    02:33 It is also approved for the prevention and treatment of osteoporosis.

    02:37 It is an antagonistic effect that reduces breast cancer risk.

    02:42 Its agonistic effect does not have any significant estrogenic effects on the endometrial tissue unlike tamoxifene which makes it a little bit better in terms of endometrial cancer risk, so itâ€(Trademark)s a very nice drug thatâ€(Trademark)s come along and starting to being starting to be picked up more and more in terms of use.

    03:03 Another drug in this drug class is bazedoxifene which is also a cousin of tamoxifene.

    03:09 You can see that these agents all end in F-I-N-E or F-E-N-E except for tamoxefen which the E is dropped for some reason that I can't explain, but generally speaking when you have that suffix thatâ€(Trademark)s the class of drugs weâ€(Trademark)re talking about, this also is used for menopausal symptoms and itâ€(Trademark)s also used for osteoporosis prevention with estrogens.

    03:33 Clomiphene is another example of a drug in this class.

    03:36 It reduces the negative feedback loop in the pituitary.

    03:41 What you end up having when you give this medication is you have an increase in the luteinizing hormone and follicular stimulating hormone.

    03:50 Why would we ever want to do that? Well, in patients who donâ€(Trademark)t have ovulation or anovulatory patients, it actually can induce ovulation.

    04:01 Now, letâ€(Trademark)s move on to the full antagonist.

    04:04 An example of the full antagonist include drugs like fulvestrant.

    04:09 It is a pure estrogen antagonist in all tissues whether youâ€(Trademark)re talking about breast or endometrium.

    04:16 So it is used in breast cancer, in patients who are resistant to tamoxifen and it is also used in patients who have breast cancer who also have high risk for endometrial cancer so although it isnâ€(Trademark)t used as much as tamoxifen it is a very good drug and you can see where it fits on our pathway here, it's right next to the tamoxifens.

    04:39 The next category of our drug are the aromatase inhibitors.

    04:43 They are also called synthesis inhibitors.

    04:45 Why do we call them synthesis inhibitors? Because if you take a look at our diagram here.

    04:50 Youâ€(Trademark)ll see the aromatase is really responsible for one of the last steps in the production of estrogen.

    04:57 Now these drugs are nonsteroidal competitive aromatase inhibitors.

    05:03 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.

    05:11 Another agent in this class is exemestane which is an irreversible aromatase inhibitor.

    05:18 Now I put it in slightly different category because it is irreversible.

    05:22 It is also used in the treatment of breast cancer.

    05:27 Letâ€(Trademark)s move on to other types of agonists specifically the gonadotropin releasing hormone antagonist.

    05:34 Now this is a complicated drug and Iâ€(Trademark)ll tell you why.

    05:37 Danazol is the prototypical drug in this drug class. There are others but letâ€(Trademark)s focus on danazol.

    05:43 Now this drug or this agent inhibits more than forty-five different enzymes that are involved in not just gonadotropin synthesis but other types of complex molecule synthesis as well so itâ€(Trademark)s a very complicated drug.

    05:57 It is metabolized by cytochrome P450 and you should be aware that it can have drug interactions.

    06:04 It is a weak partial agonist of progestin, androgen and glucocorticoid receptor so itâ€(Trademark)s a complex set of effects here.

    06:15 It is used in the treatment of endometriosis.

    06:19 It is used in the treatment of fibrocystic disease of the breast and it can be used in other dysmorphic diseases of the endometrium.

    06:28 Iâ€(Trademark)m going to move on to a slightly different category of drugs.

    06:32 These are the gonadotropin releasing hormone analogues which means that they simulate the activity of gonadotropin releasing hormone.

    06:41 The first of this that Iâ€(Trademark)m going to talk about is leuprolide.

    06:44 Now, we have discussed this in a previous lecture but Iâ€(Trademark)ll just mention it here for a completeness sake.

    06:52 This provides continuous stimulation of GnRH receptors which actually end up suppressing secretion in the long run.

    06:59 Why does that happen? Well, think about teasing your little brother or your little sister.

    07:05 Continuous teasing of your little brother or little sister eventually results in that sibling ignoring you.

    07:11 Itâ€(Trademark)s kind of the same thing with the brain and with the body.

    07:15 If you have continuous stimulation of certain types of receptor eventually, the effect of that stimulation becomes less and less.

    07:24 That happens through a processes called receptor mediated endocytosis also called down regulation, so you end up taking in those receptors and you destroy them at a higher rate than you're producing them, eventually, you have fewer receptors to respond to your stimulus and you have less of an effect.

    07:41 Now, the end result of using a drug like this is that it inhibits ovarian production of estrogen and progesterone so it is an anti-estrogen and anti-progesterone medication.

    07:53 We use this in the treatment of precocious puberty in girls.

    07:57 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.

    08:08 We also use the short term for the treatment of endometriosis, we donâ€(Trademark)t know want to use it long term for obvious reasons and we can use it short term for the treatment of fibroids as well which is kind of the same process as endometriosis.

    08:23 Letâ€(Trademark)s move on now to the gonadotropin releasing hormone antagonists.

    08:28 So ganirelix is one of the first examples that weâ€(Trademark)ll use and sometimes this is used for controlled ovarian hyperstimulation in patients who are anovulatory.

    08:37 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. Now we can use it in females as well.

    08:51 It is used in the first week of therapy with leuprolide in those patients.

    08:55 We are less likely to cause a tumor flare with this combination of leuprolide and abarelix.

    09:03 The next category of drugs are the antiprogestins, and the most famous of these is mifepristone which is also known as RU 486.

    09:12 You may remember this as being very controversial when it was first released on to the market.

    09:16 It is an antagonist of progesterone and it is also an antagonist of glucocorticoids.

    09:23 The use was for as an abortifacient and it is also given in combination with misoprostol with a 95% termination rate.

    09:33 Side effects of this particular agent include nausea, vomiting and diarrhea.

    09:38 You can also get cramping and bleeding and you may have episodes of unusual infections like clostridium for some unknown reason and we can't really explain why that happens.

    09:50 Okay, thatâ€(Trademark)s great. We covered a couple of these medications.

    09:53 Go to your exam, feel confident and show them what you know.

    About the Lecture

    The lecture Anti-Estrogens and Antiprogestins – Reproductive Pharmacology by Pravin Shukle, MD is from the course Reproductive Pharmacology. It contains the following chapters:

    • Antiestrogens – SERMs
    • Full Antagonists
    • Aromatase Inhibitors
    • Other Antiestrogens
    • Antiprogestins

    Included Quiz Questions

    1. Estrogen receptor antagonist in the breast Estrogen receptor agonist in the uterus
    2. Estrogen receptor antagonist in both the breast and uterus
    3. Estrogen receptor agonist in both the breast and uterus
    4. Estrogen receptor agonist in the breast Estrogen receptor antagonist in the uterus
    5. No affect in the breast or uterus
    1. Raloxifene
    2. Tamoxifene
    3. Medroxyprogesterone
    4. Estrogen
    5. Premarin, a therapy consisting of horse urine
    1. Increases ovulation rate
    2. Acts on the pituitary
    3. Acts as an agonist of GnRH receptors
    4. Ultimately reduces GnRH receptor function
    5. Reduces LH and FSH after continuous therapy
    1. Hirsutism
    2. Nausea
    3. Vomiting
    4. Cramping
    5. Bleeding

    Author of lecture Anti-Estrogens and Antiprogestins – Reproductive Pharmacology

     Pravin Shukle, MD

    Pravin Shukle, MD

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