SERM molecular mechanism of action

• The post in the Reddit thread in question is titled “ELI5: How do SERMs work” and is from two years ago on the subreddit explainlikeimfive.
• The poster is doing some Biology coursework, specifically on SERMs for osteoporosis and is confused about what it means for a SERM to be an agonist or antagonist.
• In response, a Reddit user says that SERMs act like oestrogen, but they don’t actually bind to the same receptors as oestrogen. They can either block or activate them depending on which type of receptor it binds to. This user has 0 karma.
• Another Redditor, with 1 karma, says that SERMs should have agonistic activity on some estrogen receptors (osteoblasts, cardiovascular system) while also having antagonistic activity on some other estrogen receptors (mammary glands, uterus). They’re useful because they can prevent osteoporosis, while not increasing the risk of breast of uterine cancer. Though bisphosphonates are the drug of choice for osteoporosis, SERMs are a secondary option.
• Yet another Reddit user, with 1 karma, explains that different SERMs have different effects. For example, Clomiphene is an antagonist in hypothalamus, used to treat infertility due to anovulation, Tamoxifen is an antagonist at breast, partial agonist at uterus, bone, and is used to treat and prevent recurrence of breast cancer and to prevent gynecomastia in patients undergoing prostate cancer therapy. Finally, Raloxifene is an antagonist at breast, uterus, but agonist at bone and is therefore primarily used to treat osteoporosis.
• The user citing different examples of SERMs being selective and “modulators” notes that selectivity depends on the tissue and that “modulator” comprises activation and inhibition.
• The source of the information is cited as First Aid for USMLE Step 1.

• ‘SERMs,’ or Selective Estrogen Receptor Modifiers, are medications designed to treat conditions such as infertility, breast cancer, and osteoporosis in cis women.
• The SERMs family of drugs includes tamoxifen, toremifene, raloxifene, and clomiphene.
• Each SERM has slightly different effects, turning on or turning off estrogen receptors depending on location – such as in breast, skin, and/or uterus cells.
• Raloxifene is approved for the prevention and treatment of osteoporosis and the prevention of breast cancer; tamoxifen is used to treat breast cancer, to prevent the disease in people at high risk, and for breast pain.
• Toremifene is FDA approved for the treatment of metastatic breast cancer, while Clomiphene is utilized in fertility medicine.
• Raloxifene, in gender-marking care, tends to be better tolerated and have fewer side effects than the others.
• Being a SERM, Raloxifene works in ways that align with gender-marking care goals – turning off estrogen receptors at the breast and uterus.
• In someone with testicles interested in gender-marking care who does not want breast development, Raloxifene can minimize the effects of estrogen at the breast and reduce breast growth.
• Raloxifene does not cross the blood-brain barrier and does not cause mental/emotional changes; if an individual’s gender-marking care goals include them, they would have to take estrogen.
• Raloxifene, in someone with ovaries interested in gender-marking care who has difficulty controlling their periods, also turns off estrogen receptors in the uterus.
• Toremifene and clomiphene do not have much use in gender-marking care.
• Side effects of Raloxifene may include swelling of the hands and feet, hot flashes, infection, joint pain, leg cramps, muscle spasms, and flu-like symptoms.
• A less common, scarier side effect is blood clots – it can cause a blood clot in 1 to 2 out of every 100 people who take it.
• A Reddit user asked if a fem leaning enby person could take estrogen and Raloxifene and not develop breasts, to which the answer was theoretically yes. However, in practice, there seems to be some small “breakthrough” breast development that is presumably less than one would see on estrogen alone.
• When asked if an

• The website is a discussion about taking a SERM during a SARM cycle from a Reddit post in “r/sarmssourcetalk”.
• The post questions whether taking a SERM during a SARM cycle is beneficial or counterproductive.
• One user mentions that “low dose (25mg) Clomid EOD beginning in the 5th week” helps to avoid the effects of suppression and allowed him to finish cycles stronger (6 karma).
• Another user mentions they would be using “nolva tho” instead of Clomid in the middle of their cycle (1 karma).
• A user advises only using SERMs if “highly suppressed and coming towards the end of the cycle” and that blood tests will provide the information necessary to know if SERMs are required (3 karma).
• A few users mention that taking a SERM/SARM cycle works great (2 karma).
• The advantages of taking SERM during SARM are that Clomid will keep testosterone production high, and some people even finish a SARM cycle with higher T than when they started. Avoiding the problems with low T is also a benefit. Disadvantages may include feeling bad, depending on the individual and SARM cycle, Clomid can be unnecessary (2 karma).
• The user who suggested 25 mg low-dose Clomid EOD clarified that they took it during their cycle, only running it one more week past the end of the cycle, equating to roughly three more doses (1 karma).
• A user agrees that SERMs should only be started “at the end of the cycle or in the middle if you feel suppressed already” (1 karma).
• A user explains that Clomid doesn’t reduce IGF-1 anywhere near as much as Nolva and that “Clomid therapy improves their bone mineral density quite a lot” (2 karma).
• One user has not used the Nolva and prefers to use Clomid, stating that it is prescribed as an off-label treatment for men with hypogonadism (1 karma).
• Another user suggests that Clomid during the SARM cycle should be 12.5mg every other day and 12.5mg per day if someone wants to boost their testosterone even higher. Clomid selectively blocks estrogen receptors, mostly in the brain (hence why brain perceives low E2, then secretes more LH). However, Clomid does NOT block estrogen binding in bone, so there will be no negative effects on bone. (2 karma).

• SERM stands for selective estrogen receptor modulator.
• Enclomiphene is a type of SERM that can raise testosterone levels in men and potentially affect estrogen levels.
• There is some disagreement among users regarding whether enclomiphene increases or decreases estrogen levels, but most users seem to agree that it antagonizes estrogen and does not have any direct action on breast tissue.
• Some users suggest that other SERMs like raloxifene and tamoxifen may be better choices for mitigating gynecomastia specifically.
• The FDA has reviewed enclomiphene as a potential drug, but it has not been approved for use as of the posting of this Reddit thread.
• Enclomiphene is an oral treatment that can be easier for patient compliance.
• Enclomiphene can be used to raise testosterone levels in men who want to increase testosterone but don’t want to use testosterone replacement therapy or for men who want to continue trying to have children.
• Enclomiphene contains two isomers: enclomiphene, which is pro-androgenic, and zuclomiphene, which is an estrogen agonist. The pure enclomiphene form is thought to be superior to regular clomiphene at treating gynecomastia.
• Some users report that enclomiphene has helped them to increase testosterone and decrease estrogen levels, while others report the opposite.
• Estrogen is a byproduct of testosterone, and the higher the testosterone level, the higher the estrogen level. Therefore, enclomiphene’s effect on estrogen levels may depend on other factors, like whether it is being used as part of a PCT after a SARM cycle or in conjunction with high doses of testosterone.

• Bazedoxifene is a selective estrogen receptor modulator (SERM) that enhances differentiation of OPCs into functional oligodendrocytes that may help to promote myelin repair.
• Researchers found that Bazedoxifene promotes the growth and maturation of oligodendrocyte precursor cells into remyelinating cells and increases myelin basic protein.
• The molecular mechanism by which Bazedoxifene promotes differentiation of OPCs is independent of estrogen receptors in the brain, so it may be effective in men as well as women.
• Bazedoxifene is already approved by the Food and Drug Administration as a treatment for vasomotor menopausal symptoms in women and has relatively few side effects.
• Rankin et al. identified Bazedoxifene from a high-throughput screen as a promising therapeutic drug for multiple sclerosis.
• Using an unbiased high-throughput screen, Bazedoxifene enhanced differentiation of OPCs into functional oligodendrocytes in both murine and human cells.
• Using an in vivo murine model of focal demyelination, Bazedoxifene enhanced OPC differentiation and remyelination.
• A massive computational data integration approach identified six possible candidate targets through which SERMs may mediate their effect on remyelination.
• EBP (encoding 3β-hydroxysteroid-Δ8,Δ7-isomerase), a key enzyme in the cholesterol biosynthesis pathway, was identified as serving key role in myelin repair.
• SERMs have previously been implicated in remyelination and neuroprotection following a focus on estrogens with underwhelming and conflicting results.
• There is a significant unmet need for patients with multiple sclerosis for the FDA-approved remyelinating therapies.
• Bazedoxifene could move from bench to bedside and stand out as a tolerable alternative to previously identified remyelinating agents and other candidates within this type of drug.
• Phase II trials may not be far away.
• TAMOXIFEN was the most successful drug to support remyelination of the OPCs however, its strong side effects, and higher risk profile for patients, made it less optimal.

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Potential side effects of SERM use

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Therapeutic applications of SERMs

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Overview of different types of SERMs and their molecular mechanism of action