Talk:Androgen backdoor pathway

Response to GA review
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)

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)

The examples on the use of the term "Clinical significance"
Here are the few releavant examples on the use of the term "Clinical significance":

Maxim Masiutin (talk) 01:02, 20 November 2023 (UTC)
 * "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)

Re-submitted to GA review
I resolved the issues that you've raised and re-submitted the article a month ago. Would you please help time to review it again? Thank you! Maxim Masiutin (talk) 12:37, 18 December 2023 (UTC)

References in the lead section
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)

Simplified figure
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") Maxim Masiutin (talk) 12:13, 1 January 2024 (UTC)
 * 1) 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.
 * 2) 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.
 * 3) 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
 * 4) "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)
 * I made a simplified diagram that is easier to understand, as you suggested. Could you please review Androgen_backdoor_pathway!? Maxim Masiutin (talk) 20:57, 2 January 2024 (UTC)


 * 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.
 * Boghog (talk) 14:45, 3 January 2024 (UTC)
 * 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)
 * 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)
 * 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)
 * I like your figure, and I agree that it is simpler and we should use it, see Androgen_backdoor_pathway. Thank you! Maxim Masiutin (talk) 01:18, 5 January 2024 (UTC)
 * I have just one concern. The picture Canonical_vs_backdoor_androgen_pathway.svg 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)
 * Just for your information, I made an even simplified version with captions matching arrow colors and explaining arrow colors. Canonical_and_backdoor_pathways_to_DHT_biosynthesis.svg Maxim Masiutin (talk) 12:00, 5 January 2024 (UTC)

I have added the enzymes to File:Canonical vs backdoor androgen pathway.svg. How does this look? Also I think we need a table to keep tract of the the gene/enzyme names. Below (based in part on Table 4B1 in Biason-Lauber) is a suggestion. Boghog (talk) 14:08, 9 January 2024 (UTC)


 * Thank you, the updated picture is very good! I thought that you wanted a table with enzyme names only, we can take it from https://en.wikiversity.org/wiki/WikiJournal_of_Medicine/Alternative_androgen_pathways#Enzymes
 * Still, the idea is very good to also mention directional preference and tissue distribution. Maxim Masiutin (talk) 14:44, 10 January 2024 (UTC)
 * Can you please add the table to the article? Or you are looking for action from my side? Please let me know how to proceed. Maxim Masiutin (talk) 06:35, 12 January 2024 (UTC)
 * @Boghog thank you very much again for your contributions. What do you think should be the next steps? Maxim Masiutin (talk) 12:04, 19 January 2024 (UTC)
 * 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)
 * @Boghog thank you, get well! Maxim Masiutin (talk) 16:02, 19 January 2024 (UTC)

Marsupial pathway
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 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)
 * Yes, I liked this name too. I wanted to refer to that study to avoid "sometimes", 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 (coined the term "backdoor pathway") or  (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)
 * 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."
 * Are such sentences appropriate for Wikipedia? Maxim Masiutin (talk) 17:15, 2 January 2024 (UTC)
 * 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)

Updates to the first schematic
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)


 * @Boghog -- thank you, now it is fine! Maxim Masiutin (talk) 21:29, 25 February 2024 (UTC)
 * Also, the key 5α-reduction steps (catalyzed by SRD5A1/2/3) highlighted in pink is a good idea, thank you! Maxim Masiutin (talk) 03:19, 26 February 2024 (UTC)

11-Oxygenated androgen backdoor biosynthesis
. 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)


 * 11KT is not produced by the backdoor pathway, only 11KDHT similarly to DHT. I will address the issues that you've raised. Maxim Masiutin (talk) 18:39, 12 March 2024 (UTC)
 * 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)
 * Let me add clarifications to the "11-Oxygenated androgen backdoor biosynthesis", and then you let me know whether it makes sense. Maxim Masiutin (talk) 18:44, 12 March 2024 (UTC)
 * 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)
 * Please see the article CYP11B1 (Steroid_11β-hydroxylase):
 * 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)
 * 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)
 * As for the 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:  /  (see Fig. 3. Classic and alternative androgen biosynthesis pathways.). D6194c-1cc (talk) 20:43, 12 March 2024 (UTC)
 * 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)
 * 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)
 * Concerning whether 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.
 * Boghog (talk) 08:54, 14 March 2024 (UTC)
 * Thank you, I explicitly inserted these quotations that you suggested as a |quote= parameter. Maxim Masiutin (talk) 13:15, 14 March 2024 (UTC)
 * 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)
 * Maxim Masiutin (talk) 13:32, 14 March 2024 (UTC)
 * I also made a quote from 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.
 * Maxim Masiutin (talk) 13:45, 14 March 2024 (UTC)

Primary and secondary backdoor pathways
At last I've found a source that describes both the primary and secondaty backdoor pathways:. 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: (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)


 * There are sources; let us first agree on the text, so that I could add appropriate sources. Maxim Masiutin (talk) 21:26, 12 March 2024 (UTC)
 * 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)
 * 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]."

- Michael V. Fiandalo, Daniel T. Gewirth, James L. Mohler 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)
 * 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)
 * 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)
 * 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)
 * 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)."

- Michael V. Fiandalo, John J. Stocking, Elena A. Pop, John H. Wilton, Krystin M. Mantione, Yun Li, Kristopher M. Attwood, Gissou Azabdaftari, Yue Wu, David S. Watt, Elizabeth M. Wilson, and James L. Mohler D6194c-1cc (talk) 12:54, 13 March 2024 (UTC)
 * I can refer to these reviews as well. Maxim Masiutin (talk) 13:28, 13 March 2024 (UTC)
 * 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)
 * 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)
 * 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)
 * 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)
 * 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.
 * Even from the picture https://en.wikiversity.org/wiki/WikiJournal_of_Medicine/Alternative_androgen_pathways#/media/File:Androgen_backdoor_pathway.svg the reaction from A4 to DHT via 5α-dione doesn't look like a backdoor (backdoor reactions look like a loop caused by this back-and-forth at 3α). Maxim Masiutin (talk) 09:12, 13 March 2024 (UTC)
 * 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.
 * @Boghog - did my explanations make sense? Maxim Masiutin (talk) 09:19, 13 March 2024 (UTC)
 * 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)
 * 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)
 * Try to fully read the seminal work by Auchus and you will understand my points. Maxim Masiutin (talk) 09:30, 13 March 2024 (UTC)
 * 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)
 * 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)
 * I asked for help at https://en.wikipedia.org/w/index.php?title=User_talk%3ADiannaa&diff=1213507382&oldid=1213445284 Maxim Masiutin (talk) 13:35, 13 March 2024 (UTC)
 * 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
 * https://ru.wikipedia.org/wiki/%D0%9E%D0%B1%D1%85%D0%BE%D0%B4%D0%BD%D1%8B%D0%B5_%D0%BF%D1%83%D1%82%D0%B8_%D0%B1%D0%B8%D0%BE%D1%81%D0%B8%D0%BD%D1%82%D0%B5%D0%B7%D0%B0_%D0%B0%D0%BD%D0%B4%D1%80%D0%BE%D0%B3%D0%B5%D0%BD%D0%BE%D0%B2_%D1%83_%D1%87%D0%B5%D0%BB%D0%BE%D0%B2%D0%B5%D0%BA%D0%B0
 * you didn't object those quotes and now you claim that I didn't give you quotations. Maxim Masiutin (talk) 13:44, 13 March 2024 (UTC)
 * I don't know what a quote you talking about. Please, provide the qoute here as we need to continue the discussion. As for copyright, it's very strange to see a researcher that doesn't know that he can legally publish quotes from copyrighted sources. See the Berne Convention for the Protection of Literary and Artistic Works and right to quote article. Generally, you need to specify the authors, the title of the work and a link. D6194c-1cc (talk) 14:14, 13 March 2024 (UTC)
 * I provided the quotes, see the quote attribute at the citations. The administrator has resolved my concerns about the quotes in these circumstances: https://en.wikipedia.org/w/index.php?title=User_talk%3ADiannaa&diff=1213509095&oldid=1213507382 Maxim Masiutin (talk) 14:26, 13 March 2024 (UTC)
 * The Wikipedia's interpretation of the notion of "extent does not exceed that justified by the purpose" is vague at Copyrights. Maxim Masiutin (talk) 14:38, 13 March 2024 (UTC)
 * 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 Teahouse/About. Maxim Masiutin (talk) 14:49, 13 March 2024 (UTC)

Referencing problems
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)


 * OK, thank you, sorry for that. Maxim Masiutin (talk) 19:18, 13 March 2024 (UTC)
 * I have fixed all the referencing problems that you've spotted. Are you now OK with that? Maxim Masiutin (talk) 20:14, 13 March 2024 (UTC)
 * Looks great, thanks! -- Mikeblas (talk) 01:14, 14 March 2024 (UTC)

Backdoor pathway to DHT biosynthesis
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)


 * In addition to that, there was a GA review at Talk:Androgen_backdoor_pathway/GA1 by User:Etriusus who also didn't object about the correctness of using the same name to define these routes, but contributed time and effort as the other people. Maxim Masiutin (talk) 16:57, 14 March 2024 (UTC)


 * . 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,  (primary; see title) and  (secondary; see caption of figure 1) support 11-oxygenated androgen biosynthesis as a backdoor pathway.  And as mentioned above,  (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)
 * @Boghog I just added yesterday and let you know, do you mean that I should add more? Maxim Masiutin (talk) 20:39, 14 March 2024 (UTC)
 * The article explicitly defines the third pathway name: "can be metabolised by the backdoor pathway to 11-ketodehydrotestosterone (11KDHT)"

- Therina du Toit, Amanda C Swart 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)
 * Why don't you suggest to split other articles in the Category of Metabolic pathways at https://en.wikipedia.org/wiki/Category:Metabolic_pathways Maxim Masiutin (talk) 23:10, 14 March 2024 (UTC)
 * 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)
 * 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)
 * There is an interesting essay at WP:SYNTHNOT. Maxim Masiutin (talk) 10:44, 15 March 2024 (UTC)

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)


 * 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)
 * By the way, the MetaCyc only lists backdoor pathway to DHT, not to 11KDHT, suggesting that the backdoor pathway to DHT is widespread and commonly agreed on (as described in 2004 by Auchus) but since the backdoor pathway to 11KHDT was chategarized about 10 years later, there is not yet that in MetaCyc: https://metacyc.org/META/NEW-IMAGE?type=PATHWAY&object=PWY-8200&detail-level=2 Maxim Masiutin (talk) 15:06, 15 March 2024 (UTC)
 * Please don't ping me again. I am through editing or commenting on this article. Boghog (talk) 15:29, 15 March 2024 (UTC)