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.
The image: File:Backdoor-11-oxygenated.svg is minimized to the point of being unreadable. If possible, set the pathway longways, similar to Pantothenic acid#Synthesis, it's current state doesn't contribute much to the overall page.
Not thrilled to see a Wikijournal citation used, especially since it's used in a redundant manner. The notes sectional already links to this article.
- Furthermore, the notes say that text from the journal is incorporated into the article as a whole but fails to cite where this is specifically. Not even a footnote, please be more granular with the citations. My point here is commit to using it or don't.
Yikes, a lot of unsourced material here.
Unsourced passages:
but remain important molecules in this context since they act as androgen precursors.
The backdoor pathways to 11-oxygenated androgens can be broadly as two Δ4 steroid entry points (17-OHP and P4) that can undergo a common sequence of three transformations:
However, these AKR1C2/AKR1C4 variants leading to DSD are rare and have been only so far reported in just those two families.[42] This case study emphasizes the role of AKR1C2/4 in the alternative androgen pathways.
... as it is a common convention and emphasizes it as the 3α-reduced derivative of DHT. The function of 3α-diol was not known at that time.
demonstrated that an overlapping novel pathway is operating in mouse testes, generalizing what had been demonstrated in tammar wallaby: P4 → 5α-DHP → AlloP5→ 5α-Pdiol → AST → 3α-diol.
...attributed the urinary metabolites to the androgen backdoor pathway from 17-OHP to DHT in patients with steroid 21-hydroxylase (encoded by the gene CYP21A2) enzyme deficiency.
-I don't understand why the citations are placed at the "et al" section, I assume that these are some of the missing citations (The latter 3), but they are placed in a rather strange location that is non-compliant with MOS.
opened new avenues for understanding the biosynthesis of androgens in humans. specify how
So, as a whole, the Introduction is serving the role that the Lead should have. You can't have big sweeping statements, such as Understanding these pathways is critical for the development of effective treatments for conditions related to androgen biosynthesis. in an article's body, this is lead material.
" finally converted" removed 'finally'
leads to early male sexual differentiation how?
by even a mild increase in circulating 17-OHP levels awkward to read.
'17OHDHP' change to "Referred to as 17OHDHP or 17α-hydroxy-dihydroprogesterone"
"he steroids 11OHA4 and 11KA4 " introduced out of nowhere
" T" please establish what this means
This case study emphasizes the role of AKR1C2/4 in the alternative androgen pathways. weirdly formatted sentence, outside the citation technically. Can a causal link really be drawn from only 5 cases? Perhaps softer wording should be used here.
The prior sentence "The discovery of the backdoor pathway to 5α-dihydrotestosterone in the tammar wallaby in 2003" Doesn't mention the work done in 2000.
The History section as a whole should be simplified somewhat, we don't need a step-by-step methodology, just the high points.
The article as a whole never really establishes what the classical pathway is, just a couple of snippets here and there on some differences. That would make an excellent background section.
I apologize but this is going to be a fail from me. I can overlook prose issues but there are entire sentences that are uncited, and the MOS is all over the place at times. This isn't meant to scare you away, trust me, I've had my fair share of failed GAs, this is to show what needs to be improved. I've tried to give detailed notes on what to improve before renoming, if you disagree with my suggestions, I'm more than happy to discuss in the talk page. I wish you the best, don't give up!!! 🏵️Etrius ( Us)05:01, 3 August 2023 (UTC)[reply]
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.
I resolved all the objections of the GA review except one: '"by even a mild increase in circulating 17-OHP levels" awkward to read' -- did not find out how to resolve it. --Maxim Masiutin (talk) 23:32, 17 October 2023 (UTC)[reply]
@Etriusus: As for the citations from the Wikijournal article, I used them to avoid citing underlying references to support a particular claim since the Wikijournal article is a review article in a peer-reviewed medical journal and it is considered a better source than primary research, according to WP:MEDRS. Another benefit is that you may see that claim in the source article almost in the same form. In contrast, in the underlying articles, this claim may be scattered throughout the content of that article, and some of those articles are paywalled; I have the contents of all those articles, but not all the people have the contents due to the paywall. I nominated the article again. Can you please review it again, or should I wait for somebody else (maybe even you) to review it according to a queue position? --Maxim Masiutin (talk) 14:26, 19 October 2023 (UTC)[reply]
The examples on the use of the term "Clinical significance"
Here are the few releavant examples on the use of the term "Clinical significance":
"Clinical significance of 11-oxygenated androgens" (PMID: 28234803)
"Sex Hormone Binding Globulin: Origin, Function and Clinical Significance" (doi: 10.1177/000456329002700603)
"Clinical significance of disturbed calcium metabolism" (PMID: 21932554)
"Clinical significance of the estrogen-modifying enzymes steroid sulfatase and estrogen sulfotransferase in epithelial ovarian cancer" (PMID: 28588698)
"The clinical significance of 11-oxygenated C19 steroids has also been explored in polycystic ovary syndrome (PCOS), where 11-oxygenated C19 steroids are increased and correlate with markers of metabolic risk..." (PMID: 31175123)
"Even a minor change in the level of circulating cortisol may have physiological and clinical significance in GC homeostasis and GC-related disorders. Knowledge of the action mechanisms of GC and analysis of their effects is therefore of essential importance, especially since natural and synthetic GC are widely used in the therapy of GC-responsive diseases" (DOI: 10.2174/187152206777435582)
"...the 5α-dione pathway and pathways to 11-oxygenated steroids. A brief history of what led to the discovery of these pathways, basic information about the steroids and proteins involved in their biosynthesis as well as a summary of clinically significant findings is provided. " (doi: 10.15347/WJM/2023.003)
"The length of the CAG repeats have recently been shown to be of clinical significance in relation to phenotypic features of androgen deficiency, bone mineral density, and lipid profiles (22–24). Ethnic variation in CAG repeats have been reported with blacks having the shortest and Asians the longest CAG repeat lengths (25)" (doi: doi.org/10.1210/jc.2007-1085)
In this article, let us please not put the references in the lead section. If there is a claim that needs to be backed up by references, please make a longer version of this claim with references in the article body and a shorter version without references in the article lead. Maxim Masiutin (talk) 09:46, 1 January 2024 (UTC)[reply]
@Boghog: you mentioned that the figures are way more complicated than they need to be be. In particular, you mentioned that the Figure 2 (pathways to DHT) is much more complicated than Figure 4b in "Marsupial pathway in humans" (doi:10.1016/B978-0-12-416006-4.00015-6). You also mentioned that with a total of 16 intermediates Figure 4b in "Marsupial pathway in humans" was able to summarize both the classical (lefthand side) and alternative (righthand side) pathways. You also mentioned Figure 3 (pathways to 11-oxygenated androgens), still, we cannot compare it with that simple figure that you mentioned, because that simple scheme only mentions backdoor pathways to DHT and does not cover backdoor pathways involving 11-oxygenated androgens, such as backdoor pathways to 11KDHT and 11KT.
Let me compare Figure 2 from "Androgen backdoor pathway" (call it "A") and Figure 4b in "Marsupial pathway in humans" (call it "B")
In "A", there are corticosteroids and their conversions. They are not relevant to the topic of androgen biosythnesis, so let me remove these steroids from the figure. I will do that today.
In "B", all arrows are unidirectional, whereas in "B", some arrows are bidirections. I don't think that additional arrow heads increase the complexity or understandability.
In "B", the enzymes are specified, but there are significantly fewer enzymes specified than in "A". This is because "B" was published much earlier than "A". At the time of publication of A (2023) enzymes were very well categorized, and the interconversions also (see previous item about unidirectiona or bidirectional arrow). "B" was published in 2014 and the enzymes involved were poorly understood. We should either publish all ezymes as done in "A", or do not publish the enzymes at all. Publishing only some enzymes in 2024 as was done in "B" was probably appropriate in 2014, but is not appropriate in 2024. So we cannot use the argument about the number of enzymes specified to justify the difference in simplicity
"B" has left and right captions denoting "conventional" and "backdoor" pathways. This is a good idea. I will try to put these captions too. Will try to do that today, so that we could see how it looks.
5. "B" does not cover the involvement of androstanedione (5α-dione), it was not well caracterized in 2014, but is caractirezed nowadays. 5α-reduction of A4 leads to its conversion androstanedione (5α-dione) by SRD5A1 and then directly to DHT by either HSD17B3 or AKR1C3. While this pathway is unlikely to be of biological relevance in healthy humans, it has been found operating in castration-resistant prostate cancer where SRD5A1 is upregulated. This pathway can be summarized as: A4 → 5α-dione → DHT. This pathway is not considered a "backdoor", because 5α-reduction occurs over a C19 steroid, A4, which is already androgen, not over a C21 steroid (pregnane) such as P4 of 17-OHP or their 11-oxygenated forms. Interestingly, 5α-dione can also be transformed into AST, which can then either be converted back to 5α-dione or be transformed into DHT along the common part of the backdoor pathways to DHT (i.e., via 3α-diol). Additionally, AST produced in the backdoor pathway can be converted into 5α-dione too, leading to the following chain: 17-OHP → 17OHDHP → 5α-Pdiol → AST → 5α-dione → DHT. This may be too complex to be explained in the text, but is illustrated on the scheme. "B" does not cover all this. Maxim Masiutin (talk) 13:19, 1 January 2024 (UTC)[reply]
Hi Maxim. Thanks for the new figure which I think is a significant improvement. I have the following comments:
In order to not overwhelm the reader, I think we need to consider the backdoor pathway in two parts. First part in my opinion should focus 100% on DHT pathway and not worry about the other oxygenated androgens, except to the extent that they function as essential biosynthetic DHT intermediates. It is crystal clear that DHT plays an essential role in male sexual development, but it is less clear what function the other interemediates might have. It is my impression that these other intermediates have low to no affinity for the androgen receptor and contribute little to nothing to androgen signalling, otherhand providing DHT precursors. A few such as allopregnanolone appear to act as neurosteroids. So I think it is reasonable to focus first on DHT and then later other the other intermediates.
You mention 11-oxygenated androgens above which confuses me. Did you mean 17-oxygenated androgens? None of the steroids in the figures are oxygenated at the 11-position. Testosterone, DHT, and biosynthetic intermediates are oxygenated at the 3- and 17-positions.
The captions in the figure should be simplified to "Canonical pathway" and "Backdoor pathway". Also for the captions to work, the two pathways need to be clearly divided left and right (see for example: File:Canonical vs backdoor androgen pathway.svg). In the current figure, 5αdione need to be moved to the right.
Also I find having both color coded arrows and "canonical" and "backdoor" captions redudant and somewhat confusing. I suggest using black for all arrows.
Why I ask to consider keeping the notion that the canonical or backdoor pathway is to DHT in Figure 2
The caption on Figure 2 discusses the presence of a backdoor pathway to dihydrotestosterone (DHT). This pathway is important because there are also backdoor pathways to 11-ketodihydrotestosterone (11KDHT) and 11-ketoandrostenedione (11KT), which are mentioned in Figure3.
When oxygen is added at position 11 of a steroid, either as =O or -OH, it becomes irreversible. Once a steroid has an oxygen atom at position 11, it cannot be removed. It can only switch between =O and -OH forms.
This is why I mentioned the presence of 11-oxygenated androgens (such as 11KDHT and 11KT) in Figure 3, even though they are not covered in Figure 2.
The pathways involved in these transformations are complex and involve various interconnections and conversions. For example, in the normal pathway to DHT, DHT can be deactivated to form 3a-diol. However, this reaction is reversible and can convert back into DHT. Additionally, the backdoor pathway can also produce DHT using 3a-diol as its source.
In the case of 11-oxygenated androgens shown in Figure 3, the situation is even more complicated. While conventional androgens prioritize DHT as their most potent form, for 11-oxygenated androgens, the most relevant form is actually 11KT. Although 11KDHT twice as potent as T (testosterone), with similar potency to that of DHT (dihydrotestosterone), levels 11-KDHT in target tissues are much lower compared those of DHT. That's why from 11-oxyandrogens, the main one is 11KT, whereas in conventional androgens the main one is DHT in target tissues - both have low circulation in blodd.
Furthermore unlike conventional androgens, aromatase cannot convert these oxygenated forms into estrogens. Women generally have stronger aromatase activity than men do. Therefore for women who are healthy; their main circulating androgen would be 11-KT rather than T (unlike men who has T much higher than 11KT, and who have lower 11KT than women do) due to higher concentrations three times more than T by itself or any other androgen molecules.
The the article "marsupial pathway" mainly focuses on non-11-oxygenised androgens since little was known about 11-oxygenized androgens until recently.
11-Oxygenated androgens 11β-hydroxyandrostenedione (11OHA4) and 11-ketoandrostenedione (11KA4), were known to be operating in humans since 1950s, but were initially believed to be inactive as androgens in humans but were known to be active androgens in teleost fishes.
In a groundbreaking study conducted by Rege et al. in 2013, it was discovered that both 11-ketodihydrotestosterone (11KT) and 11β-hydroxytestosterone (11OHT) can activate the androgen receptor (AR), which is especially relevant forhealthy women. This finding shed light on the role of these previously overlooked substances as substrates for potent androgens.
Further research by Storbeck et al. also confirmed the existence of pathways leading to 11-oxygenated androgens, particularly in prostate cancer cell culture dependent on androgens.
A study conducted by Barnard et al. in 2017 demonstrated metabolic pathways from C21 steroids bypassing A4 and T that lead directly to production of 11-KDHT within prostate cancer cells derived from vitro cultures. These newly discovered pathways share similarities with the "backdoor" pathway associated with DHT synthesis.
That's why I ask you consider keeping the notion of DHT on Figure 2 to not confuse backdoor pathways of DHT biosynthesis with backdoor pathways of 11KT and 11KDHT biosynthesis.
On distinct androgens in distinct stages of life
Whereas in fetal development non-11-oxygenated androgens are primarily involved, in healthy women 11-oxygenated androgens are major. Also, in various deseases, 11-oxygenated androgens are major. For example, in castration-resistant prostate cancer, T levels in prostate drop by 95%, DHT only by 50% but 11-oxygenated androgens do not drop at all.
Also, some studies confirm that in women 11-oxygenated androgens to not drop with age since they are of adrenal origin, whereas conventional androgens of gonadal origins drop, but there are conflicting results between different studies.
On neurosteroids
You were correct about neurosteroids. It was hypothesized that prostate ilnessess such as CPPS are caused not by the androgens themselves but by neurosteroids sythnesized in backdoor pathways. However, I did not find yet very solid studies to confirm this, so that's why I didn't mention this in the article. Maxim Masiutin (talk) 16:14, 3 January 2024 (UTC)[reply]
P.S. Please also congratulate me: I was awarded top 10 medical editor on Wikipedia for my contributions in 2023! I am very proud for that, really! It was a great pleasure and great surprise that my medical contributions got appreciated! Maxim Masiutin (talk) 16:16, 3 January 2024 (UTC)[reply]
Congratulation on making the top ten list of medical editors. I made the list too
OK, now I understand where the 11-oxygenated steroids come in. But again, I think it is essential that figure 2 is kept as simple as possible, even if it leaves out details that are important in other contexts. The first figure should focus 100% on DHT biosynthesis leaving out all other features. Also it is essential that two pathways are easily distinquished in the figure and that the captions are simplified. Using colored arrows as in the current figure is not as effective as the right/lefthand side division as in File:Canonical vs backdoor androgen pathway.svg. If we cannot agree on what figure 2 looks like, I am afraid that we will not get very far in GAN review. Boghog (talk) 13:53, 4 January 2024 (UTC)[reply]
I have just one concern. The picture lists steroids but not enzymes, whereas the article heavily mentions enzymes?
How would a reader understand the enzymes without seeing them on the picture? Should we give 2 pictures: one simplified without enzymes and one additional, with full enzymes? Maxim Masiutin (talk) 11:14, 5 January 2024 (UTC)[reply]
Hi Maxim, I have been busy in real life and recovering from a cold, but I should be able to start the GAN process after next Tuesday. Cheers. Boghog (talk) 13:18, 19 January 2024 (UTC)[reply]
Hello Boghog! You suggested that the androgen backdoor pathway is sometimes also referred to as the "marsupial pathway", giving, as the source, the following work: doi:10.1016/B978-0-12-416006-4.00015-6
Still, it is just the title of this work. That work itself did not denote this pathway as a "marsupial pathway" inside the text. I also didn't find such notion of "marsupial pathway" anywhere.
Even if we assume that "marsupial pathway" is a pathway from 17-OHP to DHT, "marsupial pathway" is not the same as a "backdoor pathway" because "backdoor pathway" is a collective term of all pathways in which first step is a 5a-reduction of a pregnane, such as 17-OHP, P4, or their 11-oxygenated variants, such as 11OHP4, 11KP4, 21dF, 21dE.
Whereas in tammar wallaby the main pathway is that from 17-OHP to DHT because in tammar wallaby sexuai differentiation occurs after birth, in some "conventional" mammals, such as humans or rats (but not mice), sexuai differentiation takes place inside the placenta, and the main feedstock of DHT is not 17-OHP but P4, so that the chain of reactions is mostly a 5a-reduction of P4 rather than 17-OHP.
Still, the source that you provided is very good because it explains very well biological development in general terms, and on main points.
Still, when it comes to particular details enzymes and steroids, the study you mentioned has some deficiencies, still, I am not competent to proof these deficiencies; I worked with a coauthor who is an expert in molecular biology, but I am not, and since he was banned on Wikipedia from all sex-related issues, he no longere is involved in Wikipedia, therefore, I cannot explain why the this article has deficiencies in that respect.
I will use it as an additional reference to support some general claims.
Still, would you mind if we remove the claim that the backdoor pathway is sometimes[specify] referred to as a marsupial pathway? Maxim Masiutin (talk) 18:55, 1 Jan; uary 2024 (UTC)
OK, I removed it. I thought it was useful since it indicates in what species the alternative pathway was first discovered. Boghog (talk) 15:33, 2 January 2024 (UTC)[reply]
Yes, I liked this name too. I wanted to refer to that study to avoid "sometimes[specify]", but that study is not a "fundamental", so it would not have been a neutral point of view. An example of a fundamental study is PMID15519890 (coined the term "backdoor pathway") or PMID22170725 (demonstrated clinical relevance of this pathway in adults for the first time when attributed the urinary metabolites to the androgen backdoor pathway from 17OHP to DHT in patients with steroid 21-hydroxylase enzyme deficiency), and so on. Still, the study "marsupial pathway" explains biological processes very well, but is not ground-breaking per se. Maxim Masiutin (talk) 17:07, 2 January 2024 (UTC)[reply]
Even though, I liked the term "marsupial pathway" very much. I left the following sentence in a middle of the body article:
"That's why the backdoor pathway of DHT biosynthesis from 17OHP can be called a marsupial pathway."
Thanks for your reply. Sorry for not replying soon, but I am recovering from a severt head cold. Just to be clear, my figure is not complete. Of course it should also list the enzymes. I can add those to the figure. More later. Boghog (talk) 12:23, 6 January 2024 (UTC)[reply]
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.
OK, I will take this on. This is the first GAN review that I have ever done, so I am not sure how best to do this. My preference is to take several passes starting with the overall organization, then focus on details of each of the sections, and then finally the lead. The biggest challenge as I see it is is to make this highly technical article accessible to as wide an audience as possible, especially the lead.
The function section is actually a mix of function and history. Also there is a bit of history in the importance section. My suggestion is to move all of the history to a single section. The current history is section is specific events. It would be good to start this section a general overview of the most important develpments followed by the chronological list of specific events.
I also think having seperate function and importance sections is a bit redundant. The pathway is important because of its function. So why seperate the two?
One thing that should be emphasized is that both the cononical and backdoor pathways are required for full male sexual development. Also it is not clear what exactly is the physiological importance of the 11-oxygenated pathway. This should be clarified.
For completeness, I think the biochemistry section should be introduced by a brief section covering the canonical pathway with a
The order of the "17α-Hydroxyprogesterone pathway" and "Progesterone pathway" subsection should be flipped. As shown in figure 2, there is a subpathway that leads from progesterone to 17α-Hydroxyprogesterone so it makes sense to discuss progesterone first.
Flip the order of benign prostatic hyperplasia cancer. Hyperplasia is a precursor of cancer so it makes sense to discuss hyperplasia first.
The clinical signifance section mixes both the DHT backdoor and 11-oxygenated pathways. It would be good if possible to discuss the clinical signficance of each of the pathways seperately. Boghog (talk) 13:20, 29 January 2024 (UTC)[reply]
Sorry, I didn't notice that you left a message back than on 29 January 2024, although I am subscribed to the page "Androgen backdoor pathway". I did notice only now that that you left the message. Please give me 1 day to resolve the issues that you've identified. Thank you! Maxim Masiutin (talk) 18:05, 31 January 2024 (UTC)[reply]
I am now resolving the objections that you've noticed. The GA review should verify that the article formally meets the GA criteria; still, the interpretation of these criteria may vary between the reviewers; a GA article should not be as good as a FA article :-) Maxim Masiutin (talk) 11:27, 1 February 2024 (UTC)[reply]
The function of androgen backdoor pathways is to produce clinically significant androgens in situations where the conventional pathway is insufficient, such as in male fetal development.
I emphasized in the function that both the canonical and backdoor pathways are required for full male sexual development, by writing "The function of androgen backdoor pathways is to produce clinically significant androgens in normal conditions where the conventional pathway is insufficient, such as in male early sexual differentiation."
Still, the function of the backdoor pathways in 11-oxygenated androgen biosynthesis for normal healthy humans is unknown. It is known than 11-oxygenated androgens are are major circulating androgens in healthy women, but they are likely synthesized from T (T->11OHT->11KT) rather than via backdoor pathways.
I mentioned the essense of the canonical pathway ("In the canonical pathways of androgen biosynthesis, DHT is synthesized from T via 5α-reduction, so that 5α-reduction of T, a C19 steroid, is the last step of the pathway (see Dihydrotestosterone § Biosynthesis). In the backdoor pathways, to the contrary, 5α-reduction of C21 steroids is the first step").
I propose you to keep the order of "17α-Hydroxyprogesterone pathway" vs "Progesterone pathway", because 17α-Hydroxyprogesterone pathway is better studied and better characterized, with more information on the enzymes available.
You also mentioned that the clinical significance section mixes both the DHT backdoor and 11-oxygenated pathways, and suggested to discuss the clinical significance of each of the pathways seperately, still, these pathways are only activated in pathological conditions, and they are likely activated both, so DHT is synthesized via backdoor pathways with 11KDHT, therefore, it will be problematic to discuss them separately.
I flipped cancer and hyperplasia as you suggested.
Thanks for your edits merge history into one section. That looks better.
One quick reflection on nomenclature. One needs to clearly distinquish between physiology and pathophysiology. Physiological refers to the normal functioning of an organism. Cinical (pathophysiology) refers to treating or diagnosing disease. The role of the backdoor pathway in normal sexual develop should be described as physiologically important. In contrast, a loss of function mutation in an enzyme involved in the backdoor pathway can lead to a clinically significant outcome (abnormal sexual development). My recommendation is to replace all occurrences of the word "clinically" with "physiologically", except where it is being discussed in a disease context (e.g., the clincal significance section).
Also I would appreciate if you would reconsider the order of "17α-Hydroxyprogesterone pathway" and "Progesterone pathway" sections. When I compared these two section to figure 2, I was initially confused, and I have some background in this area. If I am having trouble following it, I would imagine others will as well. It would be much clearer if the "Progesterone pathway" is discussed first because that is what occurs first in the figure. And there is a good reason for the order in the figure (there is a subpathway that leads from progesterone to 17α-hydroxyprogesterone). Because of the highly technical nature of the subject, it is doubly important to make the article as easy to follow as possible. Logical flow and consistency between the text and the figures is much more important than which section has been more throughly studied. More later. Boghog (talk) 07:11, 2 February 2024 (UTC)[reply]
OK, I swapped the order of these pathways, although it required editing, as the second pathway proceeded the same way as the first pathway after a certain point. Maxim Masiutin (talk) 18:24, 4 February 2024 (UTC)[reply]
Therefore, I hope I resolved all the issues that you've identified. The only remaining questions are about the issues you mentioned were identified in the initial review, however, I thought I already resolved them, as I made edits, for example, explained the term feedstock, etc. As for the sentence "this route may be activated regardless of age and sex by even a mild increase in circulating 17OHP levels", I don't understand why do you think that it is awkward to read. This sentence is grammatically correct. It correctly uses the phrase "regardless of" to indicate that age and sex do not affect the activation of the route, and the preposition "by" to specify what causes the activation (a mild increase in circulating steroid levels). Maxim Masiutin (talk) 16:11, 5 February 2024 (UTC)[reply]
I looked into Talk:Androgen backdoor pathway and Talk:Androgen backdoor pathway/GA2 and don't see any message from you. The GA review process is expected to be a light process, the article should just comply to GA requirements, even if there is room for improvement or the article is not good enough per se (apart from compliance to GA requirements). There are FA requirements which is a next step, they are more stringent. Because the GA process is intended to be lightweight, it is expected to complete in 7 days. Do you have any other todo if you think that the article does not yet meet the GA requirements? Maxim Masiutin (talk) 15:41, 10 February 2024 (UTC)[reply]
Thank you for splitting information into the subsections. It is always beneficial to have subsections. We may have future ideas on how to improve the article. The article is not "static" related to GA assessment, it can be further improved. Maxim Masiutin (talk) 21:15, 11 February 2024 (UTC)[reply]
Just to be clear, in addition to adding subheadings, the material was also reorganized, and the current first paragraph was copyedited. All of this is part of the GAN review. Per WP:GAN/I#R3, "if the problems are easy to resolve, you may be bold and fix them yourself." Boghog (talk) 09:05, 12 February 2024 (UTC)[reply]
Hi, sorry for the delay. Thanks for the changes made above which I think are an improvement. I have a few more points on organization:
Function section: I was bold and moved parts of the function section that are actually about function to the first paragraph. The rest of the section is not really about function. Instead the remainder of the section describes how androgen signaling works, the steps in the pathway, nomenclature, and pathology. I wasn't sure where to move it, so I temporarily moved it to a "androgen signaling" and "biocheimcal signifance" sections.
"Development of the reproductive system" (implies normal physiology) section heading should be renamed to "Undervirilization" (denoting a pathology) or something similar. More later. Boghog (talk) 20:05, 11 February 2024 (UTC)[reply]
The biosynthesis of 11KT and 11KDHT from intermediates of the classical pathway are well established (see for example the dark blue portion of figure 3 in PMID31362062). Turning to the "11-Oxygenated androgen backdoor biosynthesis" and "Figure 3", it is claimed that the backdoor pathway provides a route to the 11-oxygenated androgens 11KT and 11KDHT. In the WikiJournal of Medicine Peer review 2 states ...the backdoor pathway is a pathway that only occurs under certain conditions. Although only recently discovered in humans, we now know that the 11-oxygenated androgen pathway functions in all healthy adults, and thus it is not a backdoor pathway as it does not require a specific set of conditions to operate.. This point was never really addressed in the response to peer review nor the final version of the WikiJournal of Medicinen article. It is also important to point out that the figure in the WikiJournal of Medicine article provides both canonical and backdoor routes to 11KT and 11KDHT whereas File:Backdoor-11-oxygenated.svg (figure 3) provides only the hypothetical route to 11KT and 11KDHT. Figure 3 is at best misleading, since it omits mention of the classical pathway and at worst, is original research. Is there any reliable source that supports that in either in the normal or a disease state, the backdoor pathway provides a signficant amount of 11KT and 11KDHT? Boghog (talk) 07:06, 12 February 2024 (UTC)[reply]
On more careful inspection, Figure 3 of PMID31362062 does support both the cananocial (from DHEA) and backdoor (from 5α-Pdiol/5α-17HP) pathways to 11KT and 11KDHT. Figure 3 of PMID31362062 (a total of 12 structures starting from DHEA and 5α-Pdiol/5α-17HP) is a lot simpler than File:Backdoor-11-oxygenated.svg (26 structures) and easier to follow (no structures are connect by long arrows). Are there any literature supported sub pathways that are not included in Figure 3 of PMID31362062? Boghog (talk) 10:52, 12 February 2024 (UTC)[reply]
@Maxim Masiutin: I am getting lost with the C11-oxy backdoor pathway and we really need to simplify in order to make it suitable for a good article. File:Backdoor-11-oxygenated.svg (figure 3) is unwidlely and it needs to be replaced. The right hand side of Figure 1 of PMID28774496 looks like a reasonable template. Also it would be helpful to have a schematic overview of the entire article. Here is a suggestion: File:Androgen backdoor schematic.svg that emphasizes the following (correct me if any of this is wrong): (1) the backdoor pathway is only relevant in embronic development, (2) the C11-oxy backdoor pathway is only relevant in certain disease states, (3) only 11KDHT and not 11KT is produced by the C11-oxy backdoor pathway, and (4) the cononical pathway can also produce C11-oxy androgens. Please let me know what you think. Boghog (talk) 20:50, 14 February 2024 (UTC)[reply]
If you think we need a simplification, without the full specification of all steps in pathways, than "Androgen backdoor schematic.svg" should be OK except the arrow from DHT to 11KDHT which I don't understand, and I'm not sure about the (4) ("the canonical pathway can also produce C11-oxy androgens"). I never read anywehre that the canonical pathway can also produce C11-oxy androgens, since, the canonical pathway, by definition, only speaks about the production of T and DHT. The C11-oxy androgens in humans as relevant and potent androgens have only been discovered recently, therefore anything related to C11-oxy androgens cannot be called canonical, i.e. forming a canon, which is a dogma, an accepted principle or rule. The only dogma I found in the literature, or what was called a "dogma" is that testosterone is the main androgen converted to DHT in target tissues. For example, see PMID28234803: Although the dogma that T and DHT are the dominant androgens in human beings has prevailed, this paradigm applies only to normal men. The work PMID28774496 that you referred does not tell anything about supposed direct conversion from DHT to 11-OHDHT to 11-KDHT. Therefore, I like the table "Androgen backdoor schematic.svg", but I don't understand the arrow from DHT to 11KDHT and I am not aware of any work that supports your statement "(4) the canonical pathway can also produce C11-oxy androgens", for me this statement looks like a self-contradictory, for the reasons I mentioned before. Maxim Masiutin (talk) 23:45, 14 February 2024 (UTC)[reply]
In addition to "(1) the backdoor pathway is only relevant in embryonic development", more pricese is that the backdoor pathway is only relevant in male sexual development during the embryonic phase, because for female development the backdoor pathway is not needed, as was shown by the people from a family with deficient genes that were needed for the backdoor pathways: women were normal and fertile, while men were infertile and had sexual organs underdeveloped (PMID21802064.
The backdoor pathways are important for the male sexual development not only in empryonic state, but also in minipuberty, which occurs predominantly in males around postnatal days 30–100. According to PMID27471148, androgen biosynthesis during minipuberty favors the backdoor pathway over the classic pathway.
Therefore, you can probably update the table adding minipuberty phase to embryonic phase, and maybe clarifying that it is only important for healthy males, rather than females. In females, the backdoor pathway is only relevant in pathogenic conditions such as CAH that leads to excessive androgen production and virilization. Maxim Masiutin (talk) 00:19, 15 February 2024 (UTC)[reply]
The intention of the simplified schematic is not to replace figure 2 & 3, but rather to supplement them with a high level overview that would be appropriate for the lead. Per your suggestion, I have updated the figure add early postnatal and male to the backdoor pathway.
Figure 3 in PMID31362062, dark blue section (lower lefthand side) shows A4 (which is part of the canonical pathway) as an intermediate leading to 3KT. Figure 1 in PMID33539964, righthand side shows the biosynthesis of 11KT and 11KDHT starting from either T or A4 (although it is part of something called 11OHA4 pathway). It is not clear to me under what conditions these transformations can occur, but nevertheless, it does appear that intermediates and products of the canoncial pathway may lead to 11-oxy androgens. I have now labeled the arrow from T to 11KDHT as the 11OHA4 pathway. Boghog (talk) 09:36, 15 February 2024 (UTC)[reply]
The reactions that you mentioned when 11-oxyandrogens are biosynthesized from A4 or T ocur in healthy women, because in women 11-oxyandrogens are primary androgens, levels of circulating 11KT in women are similar if not higher than that of T, see PMID31390028 The 11-oxyandrogens are primary androgens in women but not in men probably because 11-oxyandrogens cannot be converted by aromatase to estrogens, and since in women aromatase is "stronger" than in men, to protect androgens from the aromatase, they are converted to 11-oxyandrogens. Still, these reactions are not "backdoor", because backdoor reactions are those that are roundabout T and A4, i.e. starting from C21 steroids (progesterone, 17-OH-progesterone) with their 5-alpha-reduction. Therefore, the reactions that you described fall outside the scope of this article. If you are interested, you can see more information at https://en.wikiversity.org/wiki/WikiJournal_of_Medicine/Alternative_androgen_pathways#11-Oxygenated_Androgen_Pathways_2 ; to be specific, let me quote: "only three are known in healthy humans. A4 is synthesized in the adrenal where it can undergo 11β-hydroxylation to yield 11OHA4, an important circulating androgen precursor, which is further transformed to 11KA4 and then 11KT (primarily outside the adrenal in peripheral tissue):
A4 → 11OHA4 → 11KA4 → 11KT
This route is regarded as the primary 11-oxygenated androgen pathway in healthy humans. It is thought that the T entry point also operates in normal human physiology, but much less that A4:
T → 11OHT → 11OHA4 → 11KA4 → 11KT
T → 11OHT → 11KT
The diminished role of these pathways is supported by that fact that the adrenal produces significantly more 11OHA4 than OHT." -- there are references to other works that supports these claims in that peer-reviewed article.
@Maxim Masiutin: Now realizing that the 11-oxy backdoor pathway is important in healthy females (see for example Figure 3 in PMID32203405 where 11KT levels are comparable to or exceed testosterone levels), I have added this to the File:Androgen backdoor schematic.svg. Is this schematic accurate and not leave out any important facts? Hopefully it now gives an 20,000 foot overview of the entire article. I have also edited the function section to be compatible with the schematic. Does this look OK? Of course, feel free to edit further.
I am still struggling with figure 3 (File:Backdoor-11-oxygenated.svg). One thing that would really help is if 11KT and 11KDHT were highlighted in red or some other way. These are the most important products of the pathway and since they are not at the bottom, they get lost in this complex figure. Also are all these reactions confirmed in the literature or are any hypothetical? Can anything be trimmed from the figure? Boghog (talk) 15:32, 18 February 2024 (UTC)[reply]
Can you please remove "Healthy females" from 11-oxy backdoor and add all pathologic conditions listed in 11-oxy-backdoor to backdoor to DHT?
See my message [1] where I mentioned that in healthy women 11-oxy androgens are biosythesized in short pathways mainly from A4 and T, rather than the long backdoor pathways? Apart from that, the drawing is correct. It is a very good idea to implement this drawing. Maxim Masiutin (talk) 16:58, 18 February 2024 (UTC)[reply]
The article "Androgen backdoor pathways" does not aim to cover all steroidogenic pathways to androgens, it only aims to cover pathways that are categorized as "backdoor", i.e. from C21 steroids by their 5-alpha-reduction, roundabout of T and A4. Maxim Masiutin (talk) 17:00, 18 February 2024 (UTC)[reply]
I took out "healthy females" from the schematic and made corresponding changes in the function. I realize the article subject is backdoor pathways, but it is also important to put things in context. That is why I think it is important to state what other pathways (canonical) contribute to the formation of DHT, 11KT, and 11KDHT. I am still struggling with figure 3 (File:Backdoor-11-oxygenated.svg) Could you at a minimum, at least highlight the structures of 11KT, and 11KDHT? Boghog (talk) 19:19, 18 February 2024 (UTC)[reply]
I agree that we should highlight canonical pathways, but not the other pathways, such as 5-alpha-dione pathways that happen in prostate cancer, etc...
Do you mean that I should make background of different color for 11KDHT in the Figure 3 (Backdoor-11-oxygenated.svg)? May I only highlight 11KDHT, but not 11KT, because 11KT is not believed to be biosythesized in significant quantities via the backdoor pathway. Maxim Masiutin (talk) 19:37, 18 February 2024 (UTC)[reply]
Yes, highlighting the structure 11KDHT with a colored background would be helpful. If 11KT is not believed to be synthesized in significant quantities by this pathway, why is 11KT even included in the diagram? If 11KT is excluded, it looks like 11OHT could also be removed. What is the major subroute to 11KDHT in this pathway? Can anything else be removed? Boghog (talk) 20:06, 18 February 2024 (UTC)[reply]
17OHP is not specific to C11-oxy backdoor pathway. Both progesterone pathway and 17OHP pathways occur in normal fetus development, but the backdoor pathway to DHT in fetus from 17OHP is thought to be predominant, i.e. P4 → 17OHP → 17OHDHP → 5α-Pdiol → AST → 3α-diol → DHT is thought to be predominant in humans and marsupials and in rats, but in mice the predominant is thought to be P4 → 5α-DHP → AlloP5 → 5α-Pdiol → AST → 3α-diol → DHT.
Therefore, I'd suggest you move 17OHP from "C11-oxy backdoor" to "backdoor", and add 21dF to "C11-oxy backdoor", as shown in "Backdoor-11-oxygenated.svg": the initial steroids are 11OHP4 (from P4) and 21dF (from 17OHP) in reaction catalyzed by CYP11, as shown by the arrows, which are then reduced by SRD5A1 immediately or after conversion to their C11-oxo form by HSD11.
I didn't update the scheme yet at "Backdoor-11-oxygenated.svg", will do tomorrow.
21dF is 21-deoxycortisol.
I should also made friendlier captions in the svg, because now under 21dF is "4-Pregnene-11β,17α-diol-3,20-dione", probably I have to add 21-deoxycortisol, but keep that complex name in parenthesis (there is enough space) because the complex name demonstrates the structure of the steroid.
See quote from the section that I wrote for Steroid#Naming convention: "Unsaturated carbons (generally, ones that are part of a double bond) in the steroid nucleus are indicated by changing -ane to -ene.[21] This change was traditionally done in the parent name, adding a prefix to denote the position, with or without Δ (Greek capital delta) which designates unsaturation, for example, 4-pregnene-11β,17α-diol-3,20-dione (also Δ4-pregnene-11β,17α-diol-3,20-dione) or 4-androstene-3,11,17-trione (also Δ4-androstene-3,11,17-trione)." Maxim Masiutin (talk) 00:49, 19 February 2024 (UTC)[reply]
I also modified the caption to match the diagram, quote: "The backdoor pathways from progesterone or 17α-hydroxyprogesterone to 11-ketodihydrotestosterone (rose background)...".
In the initial version, there was simply the word "feedstock", and after the first GA review, I have added after the work feedstock the explanation "that is, a starting point, the initial substrate". Do you mean that I should delete the word "feedstock" altogether even though I added an explanation?
As for the word "canonical", it was not not defined in the initial revision, of the article, i.e. in the article that existed before the first review. After the first review, I defined it as an androgenic pathway that involves testosterone and/or androstenedione, and also denoted it as conventional. How would you like it it that I clarify that canonical also means "general, ideal, and/or most common" pathway? I women, it turned out to be not not the most common, it was just discovered first and denoted as such as to be opposed to the other other pathways. Also, after the first review, I emphasized that the backdoor pathway is an alternative to the conventional, canonical pathway. I also mentioned that "In the canonical pathways of androgen biosynthesis, DHT is synthesized from T via 5α-reduction, so that 5α-reduction of T, a C19 steroid, is the last step of the pathway (see Dihydrotestosterone § Biosynthesis). In the backdoor pathways, to the contrary, 5α-reduction of C21 steroids is the first step."
In the initial version of the article, the phrase "in medical literature" was in different context, now it was in the "History" section that described medical studies. Still, to not be classified as WP:Weasel, I removed this phrase "medical literature".
If you would like to check whether the issues from the first GA were resolved, please take a revision of the article that existed before the first GA, because I have resolved all the issues mentioned by the editor - so you will be able to figure out that the article was not the same as it was now.
I only expressed disagreement or questions with "by even a mild increase in circulating 17-OHP levels" was "awkward to read", still, I didn't understand why it was awkward to read and I didn't understand what was wrong with this sentence - that I mentioned. Maxim Masiutin (talk) 18:46, 4 February 2024 (UTC)[reply]
If you think I should merely remove the word "feedstock" and the phrase "by even a mild increase in circulating 17-OHP levels", please let me know. Maxim Masiutin (talk) 19:50, 4 February 2024 (UTC)[reply]
Please let me know whether the objection about "by even a mild increase in circulating 17-OHP levels" is critical, and whether you have other observations. If you think that it is critical, I will try to rewrite the sentence the other way. If you have ideas or suggestions on how to rewrite it, let me know. Otherwise, please let me know whether it is critical and we can keep it as is or I should change it. Maxim Masiutin (talk) 16:42, 6 February 2024 (UTC)[reply]
Hi Maxim, instead of this: "this route may be activated regardless of age and sex by even a mild increase in circulating 17OHP levels."
Consider phrasing that line like this: "even a mild increase in circulating 17-OHP levels may activate this pathway, regardless of the patient's age and sex."
This ends up reading easier for a couple of reasons. First, substituting pathway for route helps because unlike the latter word, "pathway" is not sometimes used as a verb. When dealing with long, winding sentences like this, those "is it a noun or a verb right now?" words can really trip up your readers. Secondly, the original phrasing makes it hard to understand that "a mild increase in circulating 17-OHP levels" is a single subject/concept/thing. The phrasing I suggested makes this much more clear, I think.
I believe this page by now easily meets the criteria to be called a Good Article. I would like to request Boghog give this a Pass and grant GA status. You both can continue improving it after that is done, after all - seems like you could go for FA status with the way things are going here. Just-a-can-of-beans (talk) 06:16, 25 February 2024 (UTC)[reply]
I plead guilty to the charge of being a perfectionist ;-) I agree that the article is in pretty good shape now and will grant GA status Thanks for your hard work Maxim Masiutin in improving this article and for your comments Just-a-can-of-beans. Cheers Boghog (talk) 18:48, 25 February 2024 (UTC)[reply]
My main concerns about this submission were accessibility and organization. Given the highly technical nature of the subject, I believe the article after copyedits is now reasonably accessible. I also think the overall organization of the article has been improved so that it now flows well. The individual sections were in fairly good shape to begin with and the few rough spots have been improved through copyedits. Congratulations Maxim Masiutin on putting together this impressive article! Boghog (talk) 19:21, 25 February 2024 (UTC)[reply]
Thank you very much for all your help. My biggest proud was the initial article in the Wikijournal of Medicine where we with @Maneesh (1) summarized on steroid naming, not seen elsewhere (now this section is copied to Steroid section of Wikipedia); (2) Made a drawing of all 11-oxygenated androgen in a form not seen everywhere else, and (3) put forward a hypothesis about the role of non-classical CAH in CP/CPPS, first exposed by Dimitrakoff in 2008 but then forgotten; the biomarkers of disease control in CAH; the role of SRD5A2 in the backdoor pathway to DHT; immune response regulation.
That was a peer-reviewed article for specific audience that didn't fit the format of Wikipedia: it had to be simpler and could not contain those hypothesis. @Boghog made great contributions on making it simpler: (1) a simpler backdoor vs classic schematic to DHT; (2) Yet simmpler summary of all pathways and their health consequences in one table; (3) easy-to-understand lead and many other contributions to make the article consistent and easy to understand, yet without losing essential information. Thank you @Just-a-can-of-beans for your feedback on the overall article and for your suggestion on rewriting a sentence. Maxim Masiutin (talk) 20:03, 25 February 2024 (UTC)[reply]
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.
@Boghog:Can you please edit Androgen_backdoor_schematic.svg and move 17OHP from "C11-oxy backdoor" to "backdoor", and add 21dF to "C11-oxy backdoor", so that it will be the following cells:
Backdoor:
Progrsterone (P4)
17α-hydroxyprogesterone (17OHP)
C11-oxy backdoor:
11β-hydroxyprogesterone (11OHP4)
21-deoxycortisol (21dF)
I gave the reasoning in two paragraphs starting from "17OHP is not specific to C11-oxy backdoor pathway", but I didn't emphasize these paragraphs, so they are probably lost among other text. Maxim Masiutin (talk) 19:52, 25 February 2024 (UTC)[reply]
@Maxim Masiutin:. After rereading this section, there are three major issue. First, it needs to be made crystal clear from reliable sources (other than published in WikiJournal) that the characterization of 11-oxygenated androgen biosynthesis as a backdoor pathway is not original research. This edit provides two sources. There may be better sources. These sources need to be added to the section. Second, there is a major disconnect between Figure 1 and this section. Why isn't 11OHP4 and 21dF even mentioned in this section? Third, why isn't it mentioned that only 11KDHT but not 11KT produced by this pathway? Boghog (talk) 17:20, 12 March 2024 (UTC)[reply]
The reaction to DHT is not reversible, i.e. whereas T can be converted to DHT and 11KT can be converted to 11KDHT, but 11KDHT cannot be converted to 11KT and DHT cannot be converted to T. Also, the 11-oxygenation reaction is not reversible. 11KDHT cannot be converted to DHT, and 11KT cannot be converted to T, but T can be converted to 11KT. Maxim Masiutin (talk) 18:41, 12 March 2024 (UTC)[reply]
Please see whether now the section 11-Oxygenated androgen backdoor biosynthesis makes sense. I didn't put yet references. I wanted first to make sure that the text is OK, and after you confirm that it is OK, I will add references. Maxim Masiutin (talk) 19:06, 12 March 2024 (UTC)[reply]
It has strong activity to convert 11-deoxycortisol to cortisol, or 11-deoxycorticosterone to corticosterone;
11-deoxycortisol and 11-deoxycorticosterone are products of CYP21. If there is block in CYP21, then there is not enough 11-deoxycortisol or 11-deoxycorticosterone whereas CYP11B1 is induced by ACTH due to low cortisol.
Since CYP11B1 has medium activity wowards P4 and 17OHP, in absence of its main substrats, it begins to hydrohylate P4 and 17OHP that to 11OHP4 and 21dF, which are then processed by SRD5, that is essnetially the start of the 11-oxygenated backdoor pathway.
Just wanted to make clear for you.
Usually, 11-oxygenated backdoor pathway happens in pathogenic conditions when either CYP21 is deficient or CYP11B1 is upregulated.
In normal conditions, such is in healthy women, 11-oxygenated backdoor pathway does not start; in women there is usually a reaction when 11KT is synthesized via A4: A4 -> 11OHA4 -> 11KA4 -> 11KT -- but this is not a backdoor pathway. Maxim Masiutin (talk) 19:13, 12 March 2024 (UTC)[reply]
Maybe we can attract other editors who can check whether the text is clear for them; and I will find and put suitable references after that. Maxim Masiutin (talk) 19:48, 12 March 2024 (UTC)[reply]
As for the [2] provided by you, it doesn't contain information about primary backdoor pathway (at least free part of the article). As I understand it describes only the C11-oxy C21 backdoor pathway. But the backdoor pathway and C11-oxy C21 backdoor pathway are two separate pathways, as can be seen in this review article: [3] / [4] (see Fig. 3. Classic and alternative androgen biosynthesis pathways.). D6194c-1cc (talk) 20:43, 12 March 2024 (UTC)[reply]
I included the secondary source that you have suggested (37850096). I also replaced all the primary sources to the secondary ones except in the history section, I would like to keep them there but also add secondary sources that state same to confirm the information. Maxim Masiutin (talk) 17:39, 13 March 2024 (UTC)[reply]
I have put secondary sources to the history section as well: the seminal study mentioned in the history section is still referenced to it (primary research), but the research findings are referenced to secondary studies that reinterpret these findings. Should there be further issues, I'm commited to fix them ASAP. However, my understanding that now the article doesn't have any problem related to sourcing (i.e., no claims are backed up by primary sources). Maxim Masiutin (talk) 20:17, 13 March 2024 (UTC)[reply]
Concerning whether PMID28774496 supports the characterization of 11-oxygenated androgen biosynthesis as a backdoor pathway, here are at least two passages, that do so:
The interconversion of 21dF and 21dE by 11βHSD yielded two C11-oxy C21 steroids which our in vitro assays showed are metabolised by steroidogenic enzymes in the backdoor pathway to yield C11-oxy C19 androgens.
... the backdoor pathway may include the 5α-reduction of 21dF and 21dE in these patients and, as a consequence, the production of potent androgens, 11OHDHT and 11KDHT.
I also added a quote from this article that was present in the Russian version of this article:
The downstream metabolism of 21dF and 21dE by the enzymes in the backdoor pathway, SRD5A and AKR1C2, was investigated and the resulting novel C11‐oxy C21 steroids, 5α‐pregnan-3α,11β,17-triol-20-one (11OHPdiol) and 5α-pregnan-3α, 17-diol-11,20-dione (11KPdiol), were shown to be suitable substrates for the lyase activity of CYP17A1, resulting in the production of C11-oxy C19 steroid metabolites 11β‐hydroxyandrosterone (11OHAST) and 11‐ketoandrosterone (11KAST)
I also made a quote from PMID32007561 which by itself is a primary research, but we don't quote any research findings, we quote from this study characterization of the backdoor pathway that they did based on other studies, so this characterization is a secondary information:
[...] steroidogenic research has focused on the metabolism of the C11-oxy C21 steroids in backdoor pathway yielding potent androgens (Fig. 1). Increased activation of the pathway and elevated enzyme expression levels are more frequently reported in the human fetus and ovaries and in clinical conditions which include 21OHD and adrenocortical tumours. [...] The detection of C11-oxy steroids in clinical conditions associated with increased backdoor pathway activity led us to investigate the catalytic activity of CYP17A1 towards the C11-oxy C21 steroids potentially contributing to the androgen pool.
At last I've found a source that describes both the primary and secondaty backdoor pathways: [5]. And it indeed can be used to define both pathways. But this source is primary about prostate cancer and I don't think that it gives notability to the topic by itself. And another source, which I have already told Maxim Masiutin about: https://www.nature.com/articles/s41388-021-01737-1. Also, I found a source that explicitly says that 2 backdoor pathways exist: [6] (it's in Spanish). But those are primary sources and might not give notability to the "backdoor pathways" topic. Anyway, good article about primary and secondary pathways must mention them and explain why they are named primary and secondary (one of the sources provided by me have such information). D6194c-1cc (talk) 20:29, 12 March 2024 (UTC)[reply]
Please note that the article is only about the backdoor pathway, it doesn't follow someone else's other classifications, such as those that classify as "primary" and "secondary". Maxim Masiutin (talk) 21:27, 12 March 2024 (UTC)[reply]
The backdoor pathway to is the primary backdoor pathway (called just "backdoor pathway"):
The secondary backdoor pathway, named for its discovery after the primary backdoor pathway, is synonymous with the Sharifi “alternative” [11] and Penning “alternate” [13] backdoor pathways, and Corcoran “5α-dione” pathway [17].
If the article is only about the backdoor pathway to dihydrotestosterone as you say, then you should not describe in detail other pathways like C11-oxy C21 backdoor pathway. And you should explicitly define primary backdoor pathway in the lead (you should mention dihydrotestosterone and ditinguish it from the secondary backdoor pathway). Other pathways may be mentioned only if reliable sources describe them in context of primary backdoor pathway (like history, common features, etc). D6194c-1cc (talk) 06:08, 13 March 2024 (UTC)[reply]
The "5α-dione" pathway is not a backdoor pathway, the article Androgen backdoor pathway does not focus on pathways called alternative and "5α-dione". Maxim Masiutin (talk) 07:49, 13 March 2024 (UTC)[reply]
It is an opinion of these authors only not shared by other authors. If this opinion would have been shared by other authors, we would have specified this point of view. We don't have to react on each particular work in isolation, we have to cover on what is a common point of view in an academic consensus unless there are solid ground that different point of view have their own justification, that point of view that you quoted is neither shared by others nor is noteworthy or have a solid explanation, it also contradicts the commonly accepted notions of the backdoor pathway given by Auchus initially for the backdoor pathway to DHT which also later has been proved to be applicable for that to 11KDHT. Maxim Masiutin (talk) 08:59, 13 March 2024 (UTC)[reply]
By ignoring reviews and making your own conclusions from a few primary sources you just do original research. It's normal to do so when you want to create research article and publish it scientific journal, but you cannot do so in Wikipedia. No sources — no notability — deletion. D6194c-1cc (talk) 12:36, 13 March 2024 (UTC)[reply]
Also, one another source:
Two backdoor pathways generate DHT without using T as an intermediate. The primary and secondary backdoor pathways convert DIOL or 5α-dione, respectively, to DHT (Figure 1A).
I you want to describe all the backdoor pathways including the C11-oxy C21 backdoor pathway you need to find the source (a review) that will give this topic notability. Otherwise combining backdoor pathways with C11-oxy C21 backdoor pathway will be original research. And the article need to describe those pathways in comparison with each other. Detailed pathway reviews should be in separate articles. What amount of information will stay in the article when you will remove all the information that is written in context of a single separate pathway? D6194c-1cc (talk) 13:59, 13 March 2024 (UTC)[reply]
We can mention this opinion shared by Mohler et all, we don't need to change anything, as we have to present the majority view if the views are contradicting - the opinion of Mohler clearly contradicts to that of Auchus, Swart, and other seminal scholars in the field. Maxim Masiutin (talk) 14:30, 13 March 2024 (UTC)[reply]
Auchus and other seminal scholars state that backdoor pathways start from C21 steroids and avoid T or A4, while the so-called "secondary backdoor" pathways of Mohler violate these two core conditions. I don't know why ever Mohler called them backdoor. Maxim Masiutin (talk) 14:32, 13 March 2024 (UTC)[reply]
Also, 3α-oxidation as a final step is also the main condition imposed by Auchus, not fulfilled in the so-called "secondary backdoor" pathways of Mohler, so, if you wish, we can point to these controversies if you insist. Maxim Masiutin (talk) 14:34, 13 March 2024 (UTC)[reply]
In any backdoor pathway there is first 3α-reduction (by a 3α-hydroxysteroid dehydrogenase isozyme, such as AKR1C2 or AKR1C4)) and then, after a chain of reactions, restoration, such as side-chain cleavage by CYP17, there is the restoration of the function group at this 3α position back by 3α-oxidation (by an enzyme that has 3α-hydroxysteroid oxidase activity, such as AKR1C2, HSD17B6, HSD17B10, RDH16, RDH5, and DHRS9) hence the notion "backdoor".
In the 5α-dione pathway, the chain (A4 → 5α-dione → DHT) lacks the 3α-oxidation, hence it cannot be called as a backdoor.
To note: 3α-diol (called so to emphasize that it is a 3α-reduced derivative of DHT) is generally considered the inactive form of DHT but because the enzymatic catalysis is reversible it could be considered a potential substrate. Once DHT is converted to 3α-diol it is inactive (but can be activated again). This conversion of 3α-diol to DHT is an essential step in the backdoor pathway to DHT, that lacks in the 5α-diol pathway. From historical perspective Wilson et al demonstrated that more 3α-diol is formed from progesterone (via, from what later Auchus characterized as the backdoor pathway) than from testosterone (T->DHT->3α-diol). Thus the predominant pathway of 3α-diol formation in the testes of tammar wallaby pouch young is via 5α-pregnane-3α,17α-diol-20-one (5α-Pdiol) and androsterone (AST) as intermediates and not via A4 as an intermediate. The 5α-diol pathway, contrary, goes from A4.
Auchus clearly defined that a backdoor pathway avoids T and A4, usual intermediates in a canonical pathway. Therefreo, Fiandalo et al made a mistake calling a pathway via A4 (A4 → 5α-dione → DHT) as "backdoor". Maxim Masiutin (talk) 09:22, 13 March 2024 (UTC)[reply]
Correct are the scholars who call the pathway A4 → 5α-dione → DHT as "alternative", "alternate", or "5α-dione", and incorrect those who call it "backdoor", as they contradict to the definition given by Auchus deliberatly or indeliberately, just because they didn't understand the topic as their peer reviewers. Maxim Masiutin (talk) 09:26, 13 March 2024 (UTC)[reply]
Please, privide a quote from this source that explicitely define the backdoor pathway(s). I asked you to provide it a long time ago, so I suspect, that it does not contain such information, and you just do an original research. D6194c-1cc (talk) 12:41, 13 March 2024 (UTC)[reply]
I provided the quote via the "quote" tag today, please see the page's history, however, I'm not sure that the quote will not be deleted due to copyright violation. Please consider accessing the articles via a library rather than requesting quotes, because, apart from copyright violations that it may trigger, you may not always get enough information from the quotes. Please don't extort the editors just because you don't have access to an article, refer to WP:SOURCEACCESS instead, an editor only has to refer works by the work and page, not by quotation, if you don't want to access the material yourself, please refrain from participating in discussions for the articles for which you refuse to obtain the source yourself. Maxim Masiutin (talk) 13:26, 13 March 2024 (UTC)[reply]
You are using your rights in bad faith with ill-intent, confirming my statements that you are acting in revenge for my review of your GA nomination of Mammalian kidney. I provided the quotations in the Russian version of the article a few months ago, see the "quote" parameter at
To find the citations, first, visit the Wikipedia article titled "Androgen backdoor pathway", once you are on the article page, look for the option to "View page source." This is usually available in the top menu or sidebar. Click on it. The page source will display the underlying code that makes up the Wikipedia article. Locate the Cite Templates with the quote parameter. Within the page source, search for the "cite" templates. These templates are used to format citations and references. Specifically, focus on the templates that have a "quote" parameter. This parameter contains the actual text you're looking for. You'll find these templates near the relevant citations in the article. Identify the required quotations, so that once you have located the cite templates with the "quote" parameter, read through them. These are the sections where the quoted text appears. Note down the relevant quotations you want to use. You can also check the page history to find the quotes easy. Alternatively, you can directly scroll down to the "References" section of the article. Here, you’ll find a list of all the sources use. Look for the citations have the quotes that you are looking for. I notified you several months ago that I added quotes to the Russian version of the article where you participated, now you started to participate in the English version, so I notify you here as well. I hope you will be able to find the quotes easily. In case of further problems, please ask a question in the Teahouse at Wikipedia:Teahouse/About. Maxim Masiutin (talk) 14:49, 13 March 2024 (UTC)[reply]
@Maxim Masiutin: looks like you've made some changes to this article that introduced several referencing errors. I've removed a duplicate reference definition you added, and have removed several undefined reference errors. You might want to revisit those changes to make sure the references you intend to have in the article are there and hooked-up correctly. -- Mikeblas (talk) 19:16, 13 March 2024 (UTC)[reply]
My understanding that User:D6194c-1cc proposes to only keep information to the backdoor pathway to DHT biosynthesis, limit the scope of the article by removing all information about 11-oxygenated androgens and the backdoor pathway to 11KDHT biosythesis, and renaming the article to better address the topic, such as to "Backdoor pathway to DHT biosynthesis".
User:D6194c-1cc, please let me know if my understanding of your position is correct.
I am against limiting the scope of the article, because I think that there are sufficient studies that explain that both DHT and 11KDHT can be biosythesized the same way via a backdoor biosythesis, the only difference is the ogyxen functional group attached to carbon position 11 of the steroid nucleus, such as -OH or =O -- in rest, the pathways are the same, moreover, they fit definitions given by Auchus in 2004.
If there will be a consensus to support the posision of User:D6194c-1cc, I am OK with the consensus. I have no interest in keeping 11-oxygenated androgens, but I don't like the idea to throw away work of many people who contributed, for example, User:Maneesh, User:Boghog, to name a few, see the whole list of attribution in the page history or use "blame" tool. I'm not authorized to do that, to remove other peoples' work, because Wikipedia is a collective effort and we cannot just do what one editor User:D6194c-1cc proposes, especially when this editor is biased, as I mentioned earlier (the bias is based on my review of his GA nomination Mammalian kidney. Maxim Masiutin (talk) 16:40, 14 March 2024 (UTC)[reply]
@Maxim Masiutin and D6194c-1cc:. To me, the issue is quite simple. Either reliable sources support or do not support the characterization of 11-oxygenated androgen biosynthesis as a backdoor pathway. As a potential alternative, the 11-Oxygenated androgen backdoor biosynthesis could be split out as a separate article. However I think there is some logic in retaining this section within this article as figure 3 logically flows into figure 4. To me, PMID31626910 (primary; see title) and PMID37850096 (secondary; see caption of figure 1) support 11-oxygenated androgen biosynthesis as a backdoor pathway. And as mentioned above, PMID28774496 (primary, see quotes above) also supports this characterization. D6194c-1cc, do you agree or not agree? Maxim, please stop arguing and fix the issue by adding citations including appropriate quotations directly in the citations. Boghog (talk) 19:07, 14 March 2024 (UTC)[reply]
The PMID31626910 article explicitly defines the third pathway name:
can be metabolised by the backdoor pathway to 11-ketodehydrotestosterone (11KDHT)
— Therina du Toit, Amanda C Swart, The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone, https://pubmed.ncbi.nlm.nih.gov/31626910/
It's a different backdoor pathway then the primary backdoor pathway. Don't forget, that "backdoor pathway" just means that this pathway bypasses something. You can't merge different pathways into a single just by common name part. As example, you cannot create a "milk" article that would describe milk as white liquide that is similar to milk of mammals by its taste and color, instead milk and plant milk are separate articles because reliable sources describes them so. And you can't add a section about Bird's milk in the article abut milk because they are not related to each other. So the source must explicitly review or compare backdoor pathways to make the article notable (see "Significant coverage", which requires that no original research is needed to extract information). The definition of the article should explicitly define whether the article is about backdoor pathway to DHT or about backdoor pathway to 11KDHT. And if the article is about backdoor pathway to DHT, it should explicitly define whether it is about primary or secondary backdoor pathway. Separate article should be created about those pathways. And also, it would help researchers to sort out all the pathways and systemize them. D6194c-1cc (talk) 21:00, 14 March 2024 (UTC)[reply]
I didn't examine those article. Do you think that there are some article with original research in this category? Can you give en example? D6194c-1cc (talk) 08:41, 15 March 2024 (UTC)[reply]
There is no original research, there is grouping of several pathways in one Wikipedia article if they are similar, there is no separate article for each of the pathways, because it will require thousands of articles. Maxim Masiutin (talk) 10:39, 15 March 2024 (UTC)[reply]
I think there may be a compromise solution to this semantic question. I get that "backdoor" implies that the pathway bypasses something and there is no evidence that DHT is biosynthetically converted into 11KDHT. So from that standpoint, it does not make sense to call 11-oxygenated androgen biosynthesis as a backdoor pathway. At the same time, 11KDHT biosynthesis relies on intermediates from the DHT backdoor pathway, and as mentioned above, there are several reliable sources that describe 11KDHT biosynthesis as part of this backdoor pathway. It is common in steroid biochemistry, and for that matter most fields of science to use more than one nomenclature do describe the same phenomena. (This reminds me of a quote by Michael Ashburner that "biologists would rather share their toothbrush than share a gene name").
The relevant Wikipedia policy is WP:NPOV. If there are differences in how something is described in reliable sources, then all significant views should be proportionately represented. So, can't we write something like "11KDHT biosynthesis has been variously described as part of the backdoor synthesis pathway or as relying on synthetic intermediates from the backdoor pathway"? Boghog (talk) 14:34, 15 March 2024 (UTC)[reply]
It is not correct to say that 11KDHT biosynthesis via a backdoor pathway relies on intermediates from the DHT backdoor pathway, because in 11KDHT biosynthesis starts from 11-oxygenation of P4 or 17OHP, and then the reactions are the same, but the molecules in all these reaction have oxygen in position 11, so, technically, these are not the same intermediates. If you see, the first reaction in backdoor pathway to DHT is 5a-reduction of P4 or 17OHP by SRD5, but in a backdoor pathway to 11KDHT, P4 or 17OHP are first 11-beta-hydroxylated by CYP11 and then 5a-reduced by SRD5 and then reaction follows using the same enzymes, with eventual reversible 11β-reduction/oxidation of the ketone/alcohol (an oxo (=O) functional group or hydroxyl (−OH) functional group, respectively) by HSD11B1/HSD11B2, so that 11OHDHT becomes 11KDHT. If you mean that the common intermediates are those before P4 or 17OHP, such as cholesterol and pregnenolone, yes, they are common ancestors for all steroids. Maxim Masiutin (talk) 15:00, 15 March 2024 (UTC)[reply]
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