Talk:Selective androgen receptor modulator/GA1

GA Review

The following discussion is closed. Please do not modify it. Subsequent comments should be made on the appropriate discussion page. No further edits should be made to this discussion.

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Reviewer: Femke (talk · contribs) 12:07, 4 November 2023 (UTC)

Happy to review this. My first impression: interesting article and very well cited.

The only GA criteria I'm worried about is 1a, as the article, in particular the lead, is very difficult. Of course, many readers of an article like this can be expected to have some background in biochemistry. Still, I believe the "appropriate broad audience" of 1a also includes people from the sports world with more of a lay interest in biochemistry or medicine. A few examples (not exhaustive).

• The first sentence could be rewritten as "Selective androgen receptor modulators (SARMs) are a class of drugs".. The word ligand and androgen should be explained at first used, or for ligand, perhaps not mentioned in the lead.
• Are AAS SARMS?
• Is it necessary to mention similar to the antiandrogens bicalutamide and hydroxyflutamide in the lead?
• Research section is mostly understandable, but what is prostatic weight?
• levator ani -> where is this muscle?
• What is virilizing?
• What is transdermal administration?

I've been using ChatGPT a lot recently to help me write at an appropriate level. The prompt I used for the lead was "Can you rewrite this for a first-year medicine audience", which was quite decent. You may find it interesting too :). Would you be able to to have a critical reread and decrease difficulty where possible? —Femke 🐦 (talk) 12:07, 4 November 2023 (UTC)

1. Done
2. Most AAS are not very selective. Most SARMs are not steroids. There is a some overlap of compounds such as 17α-alkylated anabolic steroids and YK-11 that are sometimes considered both AAS and SARMs. Clarified the most important difference in the lead and added some body text to explain better
3. Removed
4. Changed to "weight of the prostate"
5. In the pelvic floor, added
6. Glossed as (masculinizing), this refers to irreversible androgenic effects such as voice drop and androgenic hair growth
7. Through the skin using a patch, clarified

I tried chatgpt and I don't think it was helpful for usefully reducing jargon without an significant loss of precision. (t · c) buidhe 16:56, 4 November 2023 (UTC)

And now starting the full review

Non-reviewer suggestion by Maxim

I have the following suggestions on how to improve the article, let me know whether you agree:

1. A clear definition would have been better, such as (quote from PMID: 37325955) "Selective androgen receptor modulators (SARMs) are ligands that bind to AR and display tissue-specific activation of its transcriptional activity." Instead, we have a description, but it does not look like a definition ("Selective androgen receptor modulators (SARMs) are a class of drugs that were developed with the intention of maintaining some of the desirable effects of androgens, such as improving bone density and increasing lean body mass, with a much lower risk of androgenic side effects than alternative therapies such as testosterone. "

2. A classification section would have been useful to clearly uncover the following characteristics (taken from PMID: 37325955 as an example):

a) SARMs fall into 2 broad structural categories—steroidal and nonsteroidal—and;

b) SARMs can act as (I) AR agonists, (II) partial agonists, or (II) antagonists.

3. Only conventional androgens are mentioned in the article such as testosterone or DHT, still, 11-oxo androgens such as 11KT and 11KDHT, with comparable potencies, are not mentioned. Maxim Masiutin (talk) 20:19, 15 November 2023 (UTC)

1. I'm not against changing the first sentence, but it needs to be something understandable to the average reader. The proposed sentence and any definition that I am able to think up would be really difficult to understand without being familiar with pharmacology and the information in the article's mechanism section.
2. This information is already covered in the mechanism section. Do you think it should also be in the article lead?
3. 11-oxo androgens are not mentioned in the sources. I looked at Google Scholar and did not find any review articles linking these compounds to SARMs.

(t · c) buidhe 05:41, 19 December 2023 (UTC)

1. We can make it look both a definition and easy to understand, such as:

Selective androgen receptor modulators (SARMs) are a type of drugs that can selectively activate the androgen receptor (AR) in certain tissues, such as muscles and bones, to increase their growth and function, while avoiding or minimizing AR receptor activation in other tissues to reduce unwanted effects of androgen excess, such as facial hair growth, acne, increased risk of diabetes, and so on. Maxim Masiutin (talk) 06:35, 19 December 2023 (UTC)

3. Please see sections 3, 4.1 and 4.2 here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9569951/ Maxim Masiutin (talk) 06:42, 19 December 2023 (UTC)

Lead

All resolved, lead is much more accessible now

The first paragraph is still quite difficult, as it's a very long sentence, which uses some jargon (androgen, androgenic, and to a lesser extend lean body mass), and some less elegant prose (were developed with the intention of maintaining some of the desirable effects). Two alternatives: "Selective Androgen Receptor Modulators (SARMs) are a class of drugs designed to mimic the effects of anabolic steroids, without some of the negative side effects. The primary goal is to enhance bone density and promote lean body mass while notably reducing activity in other areas of the body, such as the prostate, in comparison to conventional anabolic steroids. Selective Androgen Receptor Modulators (SARMs) are a class of drugs that target androgen receptors in muscle and bone tissues. Unlike traditional anabolic steroids, SARMs are designed to promote muscle growth and enhance bone density while minimizing side effects in other parts of the body. The second paragraph could then start with: "Anabolic steroids, also known as anabolic androgenic steroids (AASs) .. " In the third paragraph, you may want to focus on more common diseases, and possibly bring back the more distant applications in large diseases like Alzheimer. Of the less well-known conditions, I believe you cannot leave out cachexia, so that may require glossing or explaining in words without mentioning the jargon. Is it possible to explain side effects with less jargon? Thanks for the suggestions. One issue is that the category of AAS and SARMs are not entirely mutually exclusive. I think that a better solution might be to compare/contrast SARMs and AAS in the second paragraph only. As for the potential uses that are just suggested in research papers, it's hard to assess whether they are WP:DUE for inclusion in the lead without any empirical validation. (t · c) buidhe 06:46, 19 December 2023 (UTC) The lead (and the whole aritcle for that matter) completely misses what was one of the main intended application of SARMs. SARMS were intended for use as androgen replacement therapy (to build bone and muscle) without increased risk of prostatic hyperplasia and prostate cancer. This needs to be added to both the lead and the body of the article. The side effect section implies that only AASs can be used for androgen replacement therapy. This is false. Boghog (talk) 19:23, 19 December 2023 (UTC) I'm not sure that's accurate. as far as I know there are no studies testing the use of sarms for hypagonadism, except possibly for the one in prostate cancer patients. the side effects section reflects what it says in the cited sources. (t · c) buidhe 19:50, 19 December 2023 (UTC) You are right that SARMs were never tested in clinic for that indication, but that was clearly the original intention. For example: Zaveri NT, Murphy BJ (2007). "Nuclear hormone receptors". In Taylor JB, Triggle DJ (eds.). Comprehensive Medicinal Chemistry II. Elsevier. pp. 993–1036. doi:10.1016/B0-08-045044-X/00063-8. An SARM for the treatment of hypogonadism or osteoporosis would be an AR agonist in the muscle and bone, with minimal hypertrophic agonist effects in the prostate. The safety bar is higher for a chronic treatments such as hormone replacement therapy. The intention was to first test for other indications were there may be a more favorable risk/benefit ratio and then follow-up with hormone replacement therapy where there is a much larger market. Boghog (talk) 20:15, 19 December 2023 (UTC) After further digging, androgen replacement therapy apparently does not increase the risk of prostate cancer and may paradoxically even reduce it. This was established after SARM drug discovery was initiated. So this eliminated one of the major potential indications. So what is the use case for a SARM? This is basically a failed drug class looking for a disease. Boghog (talk) 20:41, 19 December 2023 (UTC) It says in the article what it is being developed for. "Failed" is an opinion, which I actually don't find in the sources. (t · c) buidhe 23:01, 19 December 2023 (UTC) Yes, failed is my own opinion. So far, the clinical results have been rather disappointing and no SARM has yet to reach the market. Returning to the lead sentence, do we really need a history lession before we find out what SARMs are good for? Either of the two alternative paragraphs proposed above would be a significant improvement over the current lead sentence. Concerning selectivity overlap between SARMs and AASs, this is easily fixed by comparing SARMs with non-selective AASs. For example, the suggestions above could be modified as follows: in comparison to conventional non-selective anabolic steroids. While some AASs do show some degree of selectivity due to tissue selective metabolism, the mechanism of selectivity is quite distinct from SARMs. Furthermore the degree of selectivity that dissociated AASs display is quite modest. Boghog (talk) 12:30, 20 December 2023 (UTC) A possible way forward is to switch the second and third paragraph. Would that work, buidhe? I will try to come up with suggestions to clarify the history lead paragraph, as it still requires quite a lot of effort to fully understand. —Femke 🐦 (talk) 12:08, 23 December 2023 (UTC) I think the history paragraph may read much better with an introductory sentence: SARMS can be contacted to non-selective anabolic andro.. steroids (AAS). —Femke 🐦 (talk) 12:41, 23 December 2023 (UTC) @Buidhe: just wanted to check if you'd seen my comments. —Femke 🐦 (talk) 08:56, 7 January 2024 (UTC) Yes, I've seen your comments. I'm sorry that I haven't been working on this, but honestly it is pretty demoralizing to have another editor come in during a GAN that I am working on and make a lot of changes, many of which I do not think are improvements. (t · c) buidhe 04:34, 9 January 2024 (UTC)

Mechanism

Extended content

I'm okay with this section being quite difficult, given the audience. Still: Would it possibly be beneficial to split it into history / mechanism? A large part of it seems to be about the mechanism of related compounds. Or to make subsections? Hepatotoxix just means toxic to the liver, right? The last paragraph is the key. I'm reading Macheck to understand this paragraph better, who name three hypotheses for mechanism of action: "these potential mechanisms have been that these ligands are uniquely distributed in different tissues, have tissue-specific interactions with 5α-reductase activity and/or aromatase, or elicit non-genomic molecular actions" Narayanan mention three possible mechanisms too: enzymes, Coregulator Function, and "Intracellular Signaling Cascades". Should that first mechanism also be mentioned? It seems the intro "One hypothesis is" or "Some scientists think" is missing before "SARMs are not a substrate for 5a-reductase enzyme that converts testosterone to DHT, a highly androgenic compound", as the next sentence starts with "Other researchers.." A possible wording would be: One hypothesis is that SARMs blocks the action of an enzyme called 5α-reductase. This enzyme is involved in converting testosterone to dihydrotestosterone (DHT), a more potent androgen. This enzyme is active in certain tissues like the prostate and skin, yet inactive in others such as muscle and bone. —Femke 🐦 (talk) 09:58, 5 November 2023 (UTC) Possibly, but I'm not sure that this would be beneficial because the historical information is about how the mechanism of action for SARMs differs from pre-existing drugs. Yes hepatotoxicity causes drug-induced liver injury in this case Truth be told I don't fully understand a lot of these things, so I don't feel confident explaining them in the article. There is no controversy that SARMs are not affected by the 5alpha reductase enzyme; however, I have not read that SARMs block the effect of the enzyme on T-> DHT conversion. I don't think there is any dispute so it is not an opinion based statement. (t · c) buidhe 07:17, 19 December 2023 (UTC) IMHO, the mechanism of action should be made clearer. SARMs are a type of selective receptor modulator (mixed agonist/antagonist) where ideally they act as agonists in bone and muscle (to produced an anabolic effect), and antagonists in prostate (and hence reduce or at least not increase the risk of prostate cancer). In analogy to SERMs, and in particular tamoxifen, a possible mechanism of action for SARMS is that the ratio of coactivators and corepressors differ between various tissues. In tissues where the ratio of co-activators exceeds co-represors, a mixed agonist/antagonist becomes a full agonist and in tissues where co-repressors dominate, a mixed agonist/antagonists become a full antagonist. The evidence that SERMs work and the mechanism of action of SERMs is clear cut, but less so for SARMs. I need to dig into this further. Boghog (talk) 19:02, 19 December 2023 (UTC) PMID 28624515 discusses selective recruitment of co-activators and co-repressors by SARM/androgen receptor complexes (see especially figure 3). This shows why DHT is a full agonist (does not recruit the co-repressor NCoR), and why arylpropionamide SARMs are mixed agonists/antagonists (does recruit NCoR). What is not explicitly mentioned is the relative ratios of coactivators and corepressors in muscle, bone, and prostate tissues. This may be difficult if not impossible to track down since there are dozens of coactivators and corepressors with differing affinities for the androgen receptor/ligand complexes and presumably one would need to take a weighted average of these co-factors. Boghog (talk) 19:46, 19 December 2023 (UTC)

Research

Extended content

"Much of the research on SARMs has been conducted by corporations and has not been made publicly available". Is there a more recent source on this? Not a MEDRS statement, but may have become untrue with the passing of time. can you gloss benign prostatic hyperplasia? Rest looks good. —Femke 🐦 (talk) 10:47, 5 November 2023 (UTC) Unlikely because under publishing of pharma studies is an ongoing issue affecting 75% of studies relevant to drugs approved in 2022. Done (t · c) buidhe 07:48, 19 December 2023 (UTC) Side effects/non-medical use (done) Although elevated liver enzymes caused by SARMs might indicate hepatocellular injury, it is not known if SARMs cause a significant risk of hepatoxicity -> No jargon is necessary for this sentence, I don't think including MK-677 / Ibutamoren (a growth hormone secretagogue), GW501516 / cardarine (an agonist of the PPARß/δ), and SR9009 / Stenabolic (an agonist of the Rev-Erb) --> Not sure if possible, but it would be good if these can be explained in easier terms. Reading the first paragraphs of these links doesn't make me much wiser. 64.2 percent --> That seems like an overly high precision for a survey. Better not repeat errors around significant digits and round it to 64%. Spot checks all bore out, at least where I was able to understand the article and the paper. Will likely reread sources some after my comments around mechanisms are addressed. —Femke 🐦 (talk) 13:37, 5 November 2023 (UTC) There are multiple types of drug induced liver injury; SARMs are associated with hepatocellular injury. However, I rephrased to be more clear. Added a source for additional clarification Changed to 64 percent. (t · c) buidhe 08:03, 19 December 2023 (UTC)

Status query

Femke, Maxim Masiutin, where does this review stand? I don't see any edits or page changes in over a month. What's left to do, and can we get some progress? Thank you very much. BlueMoonset (talk) 02:22, 18 December 2023 (UTC)

Good queestion. I don't know, I just made a suggestion to improve the article. I was wondering myself why the review is "stalled". Maxim Masiutin (talk) 05:41, 18 December 2023 (UTC)

@Buidhe indicated she had a busy period coming up when I started the review, but I see she's edited quite a bit recently. Buidhe, can you give us an update? —Femke 🐦 (talk) 18:50, 18 December 2023 (UTC)

I missed this review and will try to get to it soon. (t · c) buidhe 18:51, 18 December 2023 (UTC)

Thank you! I will be grateful if you also reply to my comment! Thank you in advance! Maxim Masiutin (talk) 18:54, 18 December 2023 (UTC)

Fyi: I've just moved house and don't have internet till the 29th, so will be slow to reply, as this topic is too challenging for phone editing. —Femke 🐦 (talk) 17:40, 20 December 2023 (UTC)

Verifiability issues in content added by Boghog

Leaving aside the issues with citation format, which is no longer consistent, unfortunately the added text that I was able to check has some issues with verifiability. I was not able to check the entire text, but the two areas I did check had issues.

• The text says (no source): "However SARMs are not a substrate for 5a-reductase, hence this mechanism action cannot explain the tissue selectivity of SARMs." The last citation says the opposite: "Indeed, the role of 5α-reductase appears to play a critical part in determining the tissue-specific expression of SARMs"
• "In analogy to SERMs, SARMs are mixed agonists/antagonists displaying agonist androgen receptor activity in bone and muscle and antagonist activity in other tissues such as prostate." In the cited source, no reference is made to SARMs acting as antagonists in any tissue. I believe the last two sentences in that paragraph also cannot be verified in the cited source. (t · c) buidhe 06:04, 21 December 2023 (UTC)

• There was a consistent citation style before you decided to change it. WP:OWN (I wrote the majority of this article) does not trump WP:CITEVAR. The style should be returned to the one originally established.
• The sentence "Indeed, the role of 5α-reductase appears to play a critical part in determining the tissue-specific expression of SARMs" makes absolutely no sense. SARMs are not proteins expressed in cells, they are small molecules synthesized by chemists. The author must have meant "activity" instead of "expression". The source in turn cites PMID 17339601 which states "Considering BMS-564929 is a structural derivative of nilutamide, a nonsteroidal antiandrogen that does not interact with 5α-reductase (16), it is not likely that BMS-564929 would be a 5α-reductase substrate or inhibitor." which is consistent with what I wrote. The authors go on to say "the tissue selectivity of SARMs may be more related to the tissue-specific expression of 5α-reductase and lack of interaction between SARM and 5α-reductase" which is self-contradictory and makes no sense. The authors, invoking Ockham's Razor, conclude that because there is a correlation between 5α-reductase expression and SARM agonism in tissues therefore 5α-reductase is the cause of the selectivity. Correlation does not imply causation. This is an absolutely bizzare paper. I will search to find anyone that has followed up on this line of research.

This is what we know about the androgen receptor and 5α-reductase:

• The androgen receptor is cytosolic/nuclear and 5α-reductase is membrane bound. Direct physical interaction between the two is therefore unlikely. (Note that putative membrane androgen receptors are GPCRs, not nuclear receptors and regulate through signalling transduction, not gene expression).
• SARMS are neither substrates or inhibitors of 5α-reductase PMID 17339601.
• Dalton's statement (PMID 17339601) that "existing evidence with BMS-564929 and other SARMs strongly suggests that tissue-specific expression of 5α-reductase plays an overwhelming, if not complete, role in determining the tissue selectivity of SARMs" is backed up with zero evidence beyond correlation. I also checked Dalton's subsequent papers. Other than references back to PMID 17339601, no additional evidence has been provided. Extraordinary claims require extraordinary evidence.

Lacking evidence beyond 5α-reductase expression/SARM agonist correlation and no plausible mechanism why 5α-reductase could affect SARM selectivity, PMID 17339601 must be treated as an unreliable source. Dalton is clearly an authority in the field and has done a lot of good work. But on this particular topic, IMHO he is way off the mark. Boghog (talk) 19:11, 21 December 2023 (UTC)

Consistent citation format is irrelevant to Good Articles, so I don't know why anyone is even talking about it. See Wikipedia:Good article criteria#cite note-3: "Using consistent formatting or including every element of the bibliographic material is not required". WhatamIdoing (talk) 00:21, 22 December 2023 (UTC)

• Several other papers describe SARMs as mixed agonist/antagonists. I will add an additional citation to support that. Boghog (talk) 15:26, 21 December 2023 (UTC). PMID 30503797 which is already cited states "Selective androgen receptor modulators (SARMs) are small molecule drugs that can exert varying degrees of both agonist and antagonist effects on AR in different tissues." Boghog (talk) 20:41, 21 December 2023 (UTC)

  If the review is favorably citing a "bizarre paper", why did you cite it and add it to the article? Why do you get to decide what is bizarre?

• I did not add PMID 17339601 to the article. I have added additional comments why I think PMID 17339601 is unreliable. Boghog (talk) 19:28, 21 December 2023 (UTC)

• I finally figured out what Dalton was getting at. Somewhat paradoxically, it is the lack of tissue selective activation that results in tissue selectivity. As Kicman points out, testosterone is a prohormone in prostate requiring tissue selective activation by 5alpha-reductase which results in a non-tissue selective hormone. Conversely, the lack of activation of SARMs effectively results in tissue selectivity. But this raises the more fundamental question. Why is the "super" agonist DHT required for activation of AR in prostate while the "normal" agonist testosterone sufficient for AR activation in bone and muscle? One potential explanation is again AR coregulatory proteins. Boghog (talk) 12:49, 22 December 2023 (UTC)

• You contributed to the article, however, before your recent edits I was the author of the vast majority of the article's text,having completely rewritten it. (t · c) buidhe 18:42, 21 December 2023 (UTC)

• You don't have a monoply on this article. I also was a signficant contributor to this article before your first edit. Boghog (talk) 19:30, 21 December 2023 (UTC)

  And both of you bring an amazing wealth of experience and expertise to the article, so let's focus on content a bit more :). —Femke 🐦 (talk) 12:49, 23 December 2023 (UTC)

Additional issues introduced by the latest set of edits : some of the sources cited in the "hypogonadism and hormone replacement therapy" section don't mention either. (t · c) buidhe 15:20, 21 December 2023 (UTC)

All three sources (PMID 37325955, PMID 32257854, doi:10.1016/B0-08-045044-X/00063-8) mention hypogonadism. Boghog (talk) 15:50, 21 December 2023 (UTC)

• for the record, you changed the sources after I pointed out the failed verification issues and I haven't checked the ones that were added. (t · c) buidhe 18:46, 21 December 2023 (UTC)

• For the record, I did not. The material in this section was added in a single edit. Boghog (talk) 19:21, 21 December 2023 (UTC)

  When you said that the issues were no longer present, I assumed that you must have double checked the sources and fixed them. Thanks for clarifying that this is not the case. In the article, the sentence "Phase I and II trials have provided preliminary evidience that the SARMs enobosarm and GSK2881078 (in elderly men and postmenopausal women), and OPL-88004 (prostate cancer survivors with low levels of testoserone) increase lean body mass and muscle size with little effect on the prostate demonstrating the potential of SARMs for use in hormone replacement therapy" is cited to Bhasin 2023. The source doesn't mention hormone replacement therapy and makes no mention of hypogonadism being treated with SARMs. (t · c) buidhe 02:23, 22 December 2023 (UTC)

• The paper does not explicitly state that SARMs could be used as hormone replacement therapy, but the title which read in part "Selective Androgen Receptor Modulators to Treat Functional Limitations Associated With Aging" strongly implies it. Boghog (talk) 06:14, 22 December 2023 (UTC)

  This a semantic question. All three sources cited in the section mention treating hypogonadism with SARMs. Even though the sources don't use the phrase replacement therapy explicitly, that is what is implied. Hypogonadism is the diease, replacement it is the treatment. (e.g., PMID 25621688 states "Testosterone replacement therapy is used for the treatment of age-related male hypogonadism".) Boghog (talk) 13:58, 22 December 2023 (UTC)

Finalising the review

User:buidhe: I completely understand why this is not the most motivating GA review. I always like to go in dialogue, rather than finishing the review in one go, for more difficult-to-understand articles. I think the best I can do now for you is complete the review, and give you as much time as you would like to come back to it. I’ll ask Boghog to be the first to deal with queries of text they’ve written.

• The first two paragraphs of the history section would benefit from an introductory sentence, and better connection between the sentences.
  • Maybe start with something along the lines of: “AAS are used a variety of medical conditions, but their side effects have fueled a search for a new class of drugs.”
  • Why are we talking about anti-androgens? That information should be present before we name examples. I believe it is because this type of drug has some of the advantages of androgens (AR binding), but do not have any anabolic effects.
  • What is the relation between anti-androgens and SERMS? Can we start that paragraph with the sentence about SERMS? I think the structure of the article is better now that mechanisms and history are split.
• I would consider renaming the mechanism of selectivity into mechanism and moving the text from “SARMs can be agonists, antagonists, or partial agonists..” into this section.
• I’ve done a spot check of an additional 4 sources outside of the mechanism section, no problems.
  • I have been bold and tried to incorporate the above suggestions in this edit. Boghog (talk) 21:39, 3 February 2024 (UTC)
  • In the current version, it is claimed that 17α-alkylated AAS are somewhat tissue selective. However none of the supplied sources state that. In contrast, the supplied source support that 7-α alkyl and 19-nor testosterone substitutions have increased anbolic effects. This misinterpretation may be due to a typo in figure 21.1 of Jasuja_2012 where is stated that 17-α alkyl substitutions increase anabolic activity. This is clearly a typo since the structure corresponds to 7-α alkyl substitution. Compare with figure 1 Bhasin_2009 which does not have this typo. (Also note that both figures are slopply drawn since the R group looks like it is attached to position-6, not position-7.) Finally Methyltestosterone#Pharmacodynamics is well sourced and states 17-α methyl-testosterone is not selective. I will replace 17α-alkylated with 7α-alkylated/19-nor testosterone in the text. Boghog (talk) 13:36, 4 February 2024 (UTC)

Boghog:

• can you provide a citation to the sentence starting with “SARMs are not substrates of 5α-reductase”
• Can you explain which part of the source support the following: “In tissues where coactivators are in excess (as in bone and muscle), SARMs act as agonists. Conversely, in tissues where corepressors are in excess (such as prostate), SARMs act as antagonists”? I’ve tried to find it, but find the cited source difficult to parse.
• The section uses quite old sourcing. WP:MEDDATE says there’s likely more recent reviews. Can you comment on whether some of this info may be superseded? —Femke 🐦 (talk) 17:43, 10 January 2024 (UTC)

@Femke, on the second question for Boghog, if you search in the source for the words "Previously unreported data", I think you'll find the information you're after. Figure 4 provides a nice little summary. ("Excess" might not be the best word; it's more like relatively high or low levels.) WhatamIdoing (talk) 19:02, 10 January 2024 (UTC)

• • (edit conflict) Thanks for your excellent probing questions! Hopefully I will (eventually) be able to address them. Bhasin_2009 which is already cited elsewhere in this article states "nonsteroidal SARMs do not serve as substrates for 5α-reductase". Added citation to Bhasin_2009 to support “SARMs are not substrates of 5α-reductase”.
  • Thanks @WhatamIdoing:. I was also going to mention Figure 4 in PMC 5896569 which provides a good overview of the mechanism, although they state that the SARMs are partial agonist (equivalent to a partial antagonist). And I forgot about the "Previously unreported data". Good catch.
  • There are more recent sources (e.g., PMID 37325955 that is already cited elsewhere), but they do not go into a lot of detail concerning the mechanism of selectivity. I am still looking for more recent mechanistic reviews. More later. Boghog (talk) 19:17, 10 January 2024 (UTC)
    • PMID 32257854 which is already cited elsewhere is a more recent review that supports the AR coregulator mechanism of selectivity. I have added the citation in this edit. Boghog (talk) 14:01, 13 January 2024 (UTC)

    Thanks for verifying WAID, I didn't understand that paragraph/figure sufficiently. . And thanks for working on this Boghog :). —Femke 🐦 (talk) 20:05, 10 January 2024 (UTC)

    Just commenting that regardless of any other issues, a bunch of IP editors have come on and altered various texts without citing sources appropriately. (t · c) buidhe 18:47, 24 January 2024 (UTC)

    There was one and only one recent IP editor who in this these edits added text including citations with quotations that directely supported the statements. Hence IMHO, the text was cited appropriately. Also with respect to my edits in which you stated many of which I do not think are improvements, I have directly responded to each of your concerns [(1) added Negro-Vilar 1999 quote "indications may include .. androgen replacement in elderly men", (2) rewrote Selective_androgen_receptor_modulator#5α-Reductase section to make clear that the proposed mechanism of selectivity is lack of activation by 5alpha-reductase, and (3) "SARMs are mixed agonists/antagonists" (Narayanan 2018, Solomon 2019) and also speficifying SARMs are partial agonists to antagonists in androgenic tissue]. My major contribution was to split out a mechanism of selectivity section that was specifically requested in the GAN review. Do you have any remaining concerns? As requested in the GAN review, history section needs more work. I have inserted File:AR agonist antagonist SARM.svg that I hope partially addresses that request. Boghog (talk) 21:18, 24 January 2024 (UTC)

    Nope, you need to look at the history again. (t · c) buidhe 05:22, 25 January 2024 (UTC)

  The relevant time period is from 27 August 2023 (the date of you first edit) to the present. During this period, there was one and only one IP editor 76.174.4.161 (curiously currently under a self-requested user block). This single IP user made multiple edits. Far more importantly, do you have any remaining concerns? Boghog (talk) 07:22, 25 January 2024 (UTC)

February 7 check-in

I really hope we can get this finished soon. The major outstanding issue is that of undertandability of the lead, in particular the second paragraph which introducing new jargon (non-steriodal AASs), before explaining the relationship to the topic. See my suggestion above. I will do another spot check on the IP-added text tonight. I have copy-edited directly to speed things up, but feel free to revert if you disagree. —Femke 🐦 (talk) 18:27, 7 February 2024 (UTC)

• The second paragraph of the lead is too difficult. What about the following:

  Non-selective steroidal drugs, called anabolic androgenic steroids (AAS), have been used for various medical purposes, but their side effects limit their use. In 1998, researchers discovered a new class of non-steroidal compounds, the SARMs. These compounds selectively target the androgen receptor, offering potent effects on muscle and bone with minimal impact on reproductive tissues.

  The first paragraph now contains "seminal vesicles", which is too jargonny. You can switch this out with male reprodective tissues (right?).

• I've checked 4 sources in the terminology section, and repaired minor text-source issues in one. The others checked out.
• The side effects additions from the IP show I'm out of my depth. The writing style indicates it's not quite neutral, and some of the sources are old (2007, 2012). Would be good if either of you can have a more knowledgeable look. —Femke 🐦 (talk) 20:16, 7 February 2024 (UTC)
  • Hi. I also hope that we can get this wrapped up soon. Your suggested changes to the lead sound spot on. I have no objections if you go ahead and implement them. I will take a look at the IP edits to the side effect section. Boghog (talk) 20:28, 7 February 2024 (UTC)
  • The IP edits to the side effect section I mostly agree with. The main point is that the seperation between anabolic over virilizing effects of SARMs is not specific (i.e., absolute), but rather selective. This is an important point that I think should be emphasized. Futher down, discussion of mechanism of selectivity (5α-reductase) is included which I think is misplaced. This material should be moved to the mechanism section. Also the Gao_2007 and Yarrow_2012 are older, but already cite elsewhere. I will work on this. Boghog (talk) 20:56, 7 February 2024 (UTC)
    • Moved the misplaced material in the side effects section in this edit. Gao_2007 is old, but it is by far the most complete description of the 5α-reductase mechanism that I have found. It is frequently cited, but only in passing. Looking at Yarrow_2012 more closely, the this citation is not really need here, so I removed it. Boghog (talk) 12:58, 8 February 2024 (UTC)
  • Implemented Femke's suggestions to simplify the lead in this edit. I have also tried to reduce the redundancy between the first sentence of the lead and the second sentence of the second paragraph. Boghog (talk) 11:13, 9 February 2024 (UTC)
• Among other issues :
  • The research section used to have a clear inclusion criteria. Only uses that had reached human trials received a section, as opposed to those that remained hypothetical. The new section "hypogenadism and hormone replacement therapy" only mentions trials that were already covered below in the section "bone and muscle wasting". Which is the only proven hormone replacement like action that SARMs provide. If the trials actually measured bone and muscle anabolic activity-and especially since SARMs were tried for bone and muscle loss not resulting from hypogenadism - it seems more precise and better supported by sources to cover it there and move hypothetical use as a treatment for low testosterone in the history section if it was relevant to the rationale for drug development.
  • Adding the drug development phase to the table is not supported by the cited sources, in my opinion. All that a published trial can tell you is the phase that the trial was run on. A drug can be in multiple phases simultaneously for multiple uses.
  • As for the last sentence in the "hypogenadism and hormone replacement therapy" section, are the sources really making a connection to SARMs? If not it's original research to include. (t · c) buidhe 05:57, 8 February 2024 (UTC)
    • The "Hypogonadism and hormone replacement therapy" subsection is included in the "Possible therapeutic applications" section. The section is not entitled "Clinical trials". The potential use of SARMs in hormone replacement therapy is obvious. Hence I think it is important to mention this potential indication and why (as already indicated in the subsection) it has not been actively pursued. There have been at least two clinical trials of SARMs in healthy older men and women (PMID 22031847, 29982690) and hypogonadism is common in this age cohort. The primary endpoint in both studies was lean body mass, hence the effect on muscle was indirectly measured. Therefore these studies provide prelimary support for the SARMs to treat age-related hypogonadism.
    • The "highest development stage" column in the table is supported by citations to AdisInsight and PatSnap which in turn include "Highest Development Phases" and "R&D Status" sections respectively that directly support the data in the table column. Furthermore, I think these are ideal sources since they are continously updated. There were two drugs however where AdisInsight coverage was insufficient, so I added two citations to ClinicalTrailsGov in this edit to provide additional support. Yes, a drug can be run in parallel clinical trials each at a different stage, but listing "highest development stage" gives a sense how advanced a drug is. Importantly, it also lists if a drug has been discontinued. Boghog (talk) 12:26, 8 February 2024 (UTC)
    • Feingold_2020 which is already cited in the same section directly links SARMs to aromatization and states why aromatization is important. Boghog (talk) 12:26, 8 February 2024 (UTC)

      I'm ready to list as a GA now, but it seems like @Buidhe is less sure about the article still meeting GA criteria. Or am I misreading your comments?

      Given the article has become more complicated since I've signed up to review, I've become quite out of my depth. So, the other option is for me to put this up for a second opinion. Let me know which option you prefer? Or am I overlooking something major here? —Femke 🐦 (talk) 20:23, 9 February 2024 (UTC)

      What was the primary endpoint of the trials? If they are only measuring lean mass, rather than anything else, it makes no sense to duplicate it in separate sections. I don't think the GA criteria allow this type of organizational issue. I still feel like the "hypogonadism" angle has been shoehorned into the article to an extent that is disproportionate to coverage in the recent medical reviews specifically about SARMs, which is what the article should be based on. (t · c) buidhe 21:25, 9 February 2024 (UTC)

      While I see your point, I believe this is a disagreement that falls within normal editorial discretion. Multiple sources talk explicitly about hypogonadism, so that it's not immediately obvious it is, or isn't due weight. The section differs from the bone/lean mass section in describing the lack of effect on brains for instance. I do get your point on prioritizing HQRS here to inform the structure, and would consider this a requirement of FAs, rather than GAs. What about we resolve this via a WP:3O? Or asking somebody to weight in from WT:MED? —Femke 🐦 (talk) 08:53, 10 February 2024 (UTC)

      As proposed by Buidhe above, I have moved the hypogonadism subsection from the "Possible therapeutic applications" to the "History" section. I hope that removes the main objection. Boghog (talk) 10:16, 10 February 2024 (UTC)

      I see no reason not to list the article. Sorry for my tardiness this week, which didn't help with drawing this long review to a close. Thanks for both your hard work on the article: these sources aren't easy to understand, so impressive work! —Femke 🐦 (talk) 07:32, 17 February 2024 (UTC)

The discussion above is closed. Please do not modify it. Subsequent comments should be made on the appropriate discussion page. No further edits should be made to this discussion.