Reproductive Pharmacology Part 1 – Control of Reproductive Hormones, Leuprolide, Estrogens (ethinyl estradiol, DES, mestranol), Selective Estrogen Receptor Modulators, Hormone Replacement Therapy, Anastrozole/Exemestane, Progestins, Mifepristone (RU-486)
Almost to the finish line last but not least we have pharmacology hopefully this will help bring everything together for you and really help it stick so here i have two figures summarizing the hypothalamus pituitary gonadal axis the one on the left is for females while the one on the right is for males the drugs were going to talk about today will be acting somewhere
In one of these two figures so i’ll be referring back to them as we go as you may remember from endocrinology we’re talking about axes here therefore if the substance is low or deficient there should be a drug to replace it or that is an agonist to the target receptor similarly if there is too much of a compound then we should have a drug that does what either
Blocks it synthesis or is an antagonist at the target receptor quick little farm review what does an antagonist do to a receptor remember that it does not activate it it merely sits on it and prevents anything else from binding to it llewelyn looper light is a gnrh analog that can either inhibit or stimulate the anterior pituitary depending on how it’s given
Now it can be given pulsatile or intermittent dosing which acts like physiological gnrh we secrete gnrh in a pulsatile fashion so you can see right here this would be physiologic so it’s natural so loop relied stimulates the secretion of fsh and lh from the pituitary as we would then therefore is the treatment for infertility so what does continuous dosing of the
Villi do well continuous dosing effectively tires out the pituitary therefore you have suppression of the fsh and lh secretion there by dropping testosterone levels in men and estradiol levels in women and this way what conditions could be treated with this method you could think of conditions such as prostate cancer or uterine fibroids are also endometriosis i’ve
Know even when giving loop relied continuously you can see a start-up flare they like they like to use that one on the boards where it acts kind of like a gnrh agonist at the very beginning before it tires out the pituitary so this is actually really important to remember it’s common for the usmle it’s a switch drug first increases testosterone production before
It decreasing it the answer would be lucre light another one that you should know whether the gnrh agonist is also go sir ellen’s not as common as loop relied on the exam but it can’t show up so just know it so in terms of toxicities and toxicities of loop relied will include anti-androgen effects you can get the nc antigen effects such as hypogonadism also you
Can get some nausea and vomiting do you remember that loop light is the main treatment for prostate cancer as we said earlier it’s often given concomitantly in this condition with what drug though you got it floow2 mine it flew to my plus looper lied for prostate cancer all right i’ll explain more about that later when we reach that particular drug so it may be
Difficult to remember that pulsatile versus continuous effects of loopy line how i like to think about it is that pulsatile if your light is very excited and it has burst of lh and fsh with each pulse meanwhile continuous loop alight is just the same old monotonous dosing that just puts everyone down alright also helps to remember that normally the hypothalamus
Does release generation bursts whereas from an endo standpoint any supra physiologic released will have a negative feedback extinguishing hormone synthesis their mechanism of action is to bind the estrogen receptors as you could imagine by doing so they can be used for hypogonadism ovarian failure and menstrual abnormalities all these guys and it can be used for
Androgen dependent prostate cancer that’s a really interesting one it’s main uses however are and oral contraceptives ocps and hormone replacement therapy that will be mainly for postmenopausal women however there are potential adverse effects that we do need to talk about so in terms of toxicity the most notable being an increased risk of what cancer that’s
Big one and we’re talking here about endometrial cancer and breast cancer also you have an increased risk of thrombi so blood clots gotta be really careful with that one and paradoxically you have an increased risk of bleeding but this would be mainly in postmenopausal women as we’ve all heard you also have diethylstilbestrol which isn’t used anymore as it’s been
Correlated with an increased risk of what we can see right here which would be that’s right clear cell carcinoma of the vagina we don’t really see that anymore because we don’t really use that drug however on your boards they like this one so you can see it on the image now bear in mind that vaginal bleeding and postmenopausal women is endometrial cancer until
Proven otherwise therefore you must do a biopsy to rule it out generally also you don’t want to give estrogen to women with a history of dvt es or estrogen receptor-positive breast cancer the big one that we do need to talk about however is smoking smokers are gonna have an increased risk of clots if they’re taking estrogen so it’s just not a good idea if women come
In and they’re smokers and you want to give them estrogens it’s just not a good idea in general what would be the hormonal effect of continuous loop relied orga sir ellen therapy see you would get an lh and fsh first rise then fall as you get desensitization of the gnrh receptors on selective estrogen receptor modulators also called terms so these are drugs that
Have different effects on the estrogen receptors depending on where they’re located basically they can be an agonist or antagonist depending on where they bind here’s a little general farm review what is a drug called where it can serve as an agonist at times and an antagonist at other times it’s a partial agonist alrighty so if we look at this table of the serbs
One of the big ones is kwame fee so clomiphene works by inhibiting estrogen receptors in the hypothalamus normally estrogen binds estrogen receptors on the hypothalamus therefore negatively inhibiting gnrh release this reduces fsh and lh secretion from the anterior pituitary so clomiphene works by binding those estrogen receptors and preventing the negative
Feedback therefore you will have increase lh and fsh as we mentioned earlier clomiphene is a partial agonist meaning it’s still potentiates the receptor but to a lesser degree than estrogen so it’s binding is still registered as estrogen deficiency now this stimulates ovulation making clumping a good first line treatment for what condition in fertility exactly
Testable side-effects include hot flashes ovarian enlargement multiple simultaneous pregnancies and vision problems the reason behind the multiple gestation is that clomiphene causes an uncontrolled ovulation where both ovaries might just pop out a few eggs each unaware of what’s going on on the other side another sirum that is highly bored testable is tamoxifen it
Competitively binds the estrogen receptors and breast tissue now it’s used to treat and prevent recurrent estrogen receptor-positive breast cancer and pre and postmenopausal women on the other hand though it’s a partial agonist on the endometrium and is linked to what cancer el cáncer so it’s kind of a double-edged sword and has to be used with caution and if i
Told you that tamoxifen works as a receptor agonist and bone then try to recall from the musculoskeletal chapter what you learned about the effects of estrogen there do you remember that’s correct it helps prevent bone loss which is why this drug can be used for osteoporosis we don’t really use it for tamoxifen because of the drug i’m going to talk about now which
Is raloxifene so raloxifene is also served that has estrogen agonist properties on the bone it reduces resorption making it an effective treatment for osteoporosis now like tamoxifen it’s an antagonist on breast tissue so it also is used for invasive breast cancer but only in postmenopausal woman unlike tamoxifen however raloxifene is an antagonist on endometrial
Tissue and therefore it does not promote endometrial cancer let me summarize all that for you in the table so bottom line you want to know is that while tamoxifen and relaxes and are both agonist at the bone only tamoxifen is a partial agonist in the endometrium so only tamoxifen is associated with an increased risk of endometrial cancer that is raloxifene is
Not associated with endometrial cancer on the other hand tamoxifen would be safe to use in patients with the history of hysterectomy since they had no longer having endometrium so clomiphene is an estrogen receptor antagonist true or false false it is an estrogen receptor partial agnes moving on to hormone replacement therapy so we call it hrt to summarize now
It’s used to relieve or prevent menopausal symptoms such as hot flashes night sweats vaginal atrophy this boronia also which means painful sex and osteoporosis now osteoporosis as you may remember from physiology occurs because the drop in estrogen levels least a less active remodeling of the bone therefore an overall loss and bone density so you can see here the
Postmenopausal women that’s losing height her bones getting thinner and all that since menopause and it’s symptoms are characterized by low estrogen hr t’s mechanism of action is obvious you have increased estrogen which restores the estrogen levels thereby blocking osteoclast activity which would prevent breakdown via an habitual s but since unopposed estrogen is
Associated with endometrial cancer hrt is usually given as a combo of what you’ve got it estrogen and progesterone recently huge studies like the women’s health initiative showed that hrt is associated with increased risk of breast cancer and an increased cardiovascular risk so you have higher isn’t breast cancer heart attacks and strokes so most doctors use hrt
For short-term treatment of menopausal symptoms such as hot flashes and night sweats as opposed to long-term prevention of osteoporosis now you do need to be aware that vaisseau motor symptoms based on motor symptoms such as hot flashes vaginal dryness and pain beyond anything else are the most significant indication for postmenopausal hormone replacement therapy
Osteoporosis is not the answer since the cons of increased cancer is outweigh the pros of decreased fracture risk it’s only in the event of severe intractable vasomotor symptoms that hormone replacement therapy is best indicated alright so remember this one now it’s anastrozole and exiting so these guys are aromatase inhibitors do you remember what aroma taste does
It blocks in so if we have a rotate here it converts androgens to estrogens so it converts androgens – estrogens there for something like an ass result or xmas stain will be blocking that conversion now both drugs are using the adjuvant treatment of estrogen receptor-positive breast cancer and postmenopausal women they’re also used in patients who have progression
Of breast cancer despite treatment with tamoxifen so progestins work by binding the progesterone receptor and act to pose estrogen they increase the vascularization of the endometrium which is no surprise as we know progesterone as the pregnancy hormone which maintains the endometrium now projections are most commonly used how like we talked about earlier in ocps
When they’re mixed with estrogen they help suppress ovulation in combination with a surgeon as was sticking the cervical mucus and make it difficult for sperm to penetrate projections that you should remember include mid roxy progesterone it’s the active compound and drugs such as depo-provera which is the birth control shot for us emily purposes the other positions
That you should know are north in drum and lavona estriol happened to me on my exam i got there and i saw north end drone and completely forgot what class that was they for some reason they just don’t look like progesterone but remember those names all right so finally progestins are also using the treatment of endometrial cancer endometriosis and abnormal urine
Bleeding moving on from if a priest stone also known as ru-486 so if a persona is a competitive inhibitor of progestins at the progesterone receptor okay as we just said progesterone maintains pregnancy so mr. chris stone effectively terminates pregnancies it’s often administered within 24 to 72 hours prior it’s invisible so what does mr. russell do here it’s a
Pge one analog that causes uterine contractions which therefore results in passing of the products of conception this is why misoprostol is actually contraindicated for its other clinical use and pregnant patients can you tell me what that other clinical use is that’s right peptic ulcer disease so as i said earlier you would give me first stone which would block
The pregnancy and then a couple days later you give him as a pro so which is gonna make you evacuate the remnants of note mr. priest stone also has the effect of stimulating prostaglandins which sensitizes the myometrium to the effects of misoprostol administered later on so in terms of side effects what we want to remember are mainly heavy bleeding as you can
Imagine if you’re basically causing an abortion also nausea and vomiting anorexia and abdominal pain here’s another flash quiz for you guys what is the difference between misoprostol and if a first stone misery austell is a pge one analog whereas miss priss tone is a progesterone receptor antagonist
Transcribed from video
Reproductive Pharmacology Part 1 – Control of Reproductive Hormones, Leuprolide, Estrogens… By Abraham Tak Ka Man
