WikiJournal Preprints/Androgen backdoor pathway

From Wikiversity
Jump to navigation Jump to search

WikiJournal Preprints logo.svg

WikiJournal Preprints
Open access • Publication charge free • Public peer review

WikiJournal User Group is a publishing group of open-access, free-to-publish, Wikipedia-integrated academic journals. <seo title=" Wikiversity Journal User Group, WikiJournal Free to publish, Open access, Open-access, Non-profit, online journal, Public peer review "/>

<meta name='citation_doi' value=>

Article information

Author: Maxim Masiutin[i] , et al.

Maxim Masiutin, "Androgen backdoor pathway", WikiJournal Preprints, Wikidata Q100737840


The androgen backdoor pathway is a collective name for all metabolic pathways where clinically relevant androgens are synthesized with roundabout of testosterone as an intermediate product. Initially described as a route where 5α-reduction of 17α-hydroxyprogesterone ultimately leads to 5α-dihydrotestosterone, several other routes have been discovered towards 11-oxyandrogens which are potent agonists of the androgen receptors. The androgens produced by any of these routes cannot be converted by aromatase into estrogens, and may cause hyperandrogenism when the level of testosterone is normal. Ignoring these routes in the clinical evaluation of patients with hyperandrogenism may lead to diagnostic pitfalls.

Androgen backdoor pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone.
Maxim Masiutin CC-BY 4.0

The aim of the review[edit | edit source]

In 2003, a metabolic route from 17α-hydroxyprogesterone to 5α-dihydrotestosterone without testosterone intermediary was described[1], called in 2004 the "backdoor pathway"[2]. Since then, several other routes have been discovered that lead to 11-oxyandrogens[3] which are potent agonists of the androgen receptors.[4] The routes to 11-oxyandrogens have been also characterized as a "backdoor pathway".[5] Hence, the term "backdoor pathway" have been used by different authors to denote different metabolic pathways, that demonstrated lack of consensus of what this term actually means. Also, various authors used different names for the same metabolic intermediates, that made it hard to understand whether they meant the same or different substances.

The aim of this review is to unambiguously define all the metabolic intermediates named differently in various studies, and to give a clear and precise definition of the term "androgen backdoor pathway".

Definition[edit | edit source]

The present review defines the term "androgen backdoor pathway" as "a metabolic pathway where clinically relevant androgens are synthesized with roundabout of testosterone as an intermediate product".

Therefore, the androgen backdoor pathway is a collective name for all metabolic pathways where clinically relevant androgens are synthesized with roundabout of testosterone as an intermediate product. Any pathway that fits the definition "androgen backdoor pathway" is an alternative pathway to the conventional,[6] canonical[7] androgenic pathway that involves testosterone.

The route to 5α-dihydrotestosterone[edit | edit source]

The first route within the backdoor pathway can be described as 5α-reduction of 17α-hydroxyprogesterone (17-OHP) that is finally converted to 5α-dihydrotestosterone (DHT) within a set of enzymatic transformations that bypass the conventional[6] intermediates androstenedione and testosterone.[2][8]

In mammals, this route is activated during normal prenatal development and leads to early male sexual differentiation.[9][10][11] It was first described in the marsupials and later confirmed in humans.[12]

In congenital adrenal hyperplasia due to 21-hydroxylase deficiency or cytochrome P450 oxidoreductase deficiency,[13] this route may be activated regardless of age and sex by even a mild increase in circulating 17-OHP levels.[14][15]

The first step of this route is conversion of 17-OHP by 5α-reductase enzymes, the 3-oxo-5α-steroid 4-dehydrogenase type 1 (SRD5A1) and type 2 (SRD5A2), to 5α-pregnan-17α-ol-3,20-dione, also known as 17α-hydroxy-dihydroprogesterone (17‐OH-DHP).[16][13][8][9] The next two intermediate products are 5α-pregnane-3α,17α-diol-20-one (5α-pdiol) and 5α-androstan-3α-ol-17-one (androsterone).[7][15][17][16] The final step is conversion of 5α-androstane-3α,17β-diol (3α-diol) to DHT by several 3α-oxidoreductases (HSD17B6, RDH16, etc).[13][17] Hence, the 3α-diol has been proposed a marker of the backdoor pathway of DHT synthesis.[18]

Therefore, the pathway can be outlined as 17α-hydroxyprogesterone (17-OHP) → 5α-pregnan-17α-ol-3,20-dione (17‐OH-DHP) → 5α-pregnane-3α,17α-diol-20-one (5α-pdiol) → 5α-androstan-3α-ol-17-one (androsterone) → 5α-androstane-3α,17β-diol (3α-diol) → 5α-dihydrotestosterone (DHT).[19]

The routes to 11-oxyandrogens[edit | edit source]

The other routes that fall under the definition of the androgen backdoor pathway lead to production of 11-oxygenated (oxygen atom on C11 position forms a ketone group) 19-carbon steroids, also termed 11-oxyandrogens: 11-ketotestosterone and 11-ketodihydrotestosterone, which are 11-keto forms of testosterone and DHT, respectively. The synthesis of 11-oxyandrogens in this pathway does not require testosterone or DHT as intermediate products. 11-oxyandrogens are potent and clinically relevant agonists of the androgen receptors.[4] Potency of 11-ketotestosterone is similar to that of testosterone.[20] 11-ketotestosterone may serve as the main androgen for healthy women.[21]

11-oxyandrogens may be produced in physiologic quantities in healthy mammalian organisms,[21] and in excessive quantities in the pathological conditions like congenital adrenal hyperplasia due to 21-hydroxylase deficiency,[3][14][22] polycystic ovary syndrome,[5] benign prostatic hyperplasia[23] in prostate cancer[24] and disorders of sex development in neonates and in children.[25]

In congenital adrenal hyperplasia due to 21-hydroxylase deficiency, the steroid 11β-hydroxylase (11βOH) enzyme, also known is CYP11B1, stays at the initial step of 11-oxyandrogen production.[26]

There are several routes that may lead to production of 11-oxyandrogens:

  • 17-OHP is converted by 11βOH to 21-deoxycortisol, which is finally converted to 11-ketotestosterone and 11-ketodihydrotestosterone.[27][28]
  • Progesterone is converted by 11βOH to 11β-hydroxyprogesterone.[29] There are multiple studies conducted since 1987 that demonstrate increased levels of 11β-hydroxyprogesterone in congenital adrenal hyperplasia.[30][31][32] In vitro studies predict that excess of 11β-hydroxyprogesterone may ultimately leads to production of 11-ketodihydrotestosterone and 11-ketoandrosterone.[33][29][23] The in vitro catalytic activity (min−1) of 11βOH for progesterone is to 12.3, comparing to 96.8 for 11-deoxycortisol, the main substrate of 11βOH.[34]
  • Androstenedione is converted by 11βOH to 11β-hydroxyandrostenedione and then to 11-ketotestosterone and 11-ketodihydrotestosterone.[23][14]

History[edit | edit source]

In April 1987, Benjamin Eckstein and colleagues reported that 3α-diol, a direct precursor to DHT, is synthesized in immature rat testes in a pathway that predominantly involves 17-OHP but not androstenedione as an intermediate.[35]

In October 2000, Geoffrey Shaw and colleagues demonstrated that prostate formation in a marsupial (tammar wallaby pouch young) was mediated by the testicular androgen 3α-diol, which is higher in male than in female plasma during early sexual differentiation, identifying it as a key hormone in male development. They have shown that 3α-diol acts in target tissues via DHT, i.e. is converted to DHT in target tissues, so that testosterone is not the only source of DHT.[10]

In February 2003, Jean Wilson and colleagues described that DHT, a 5α-reduced androgen, can be synthesized from 17-OHP by two pathways: with and without testosterone as an intermediate. They have demonstrated that 3α-diol, a precursor to DHT, is formed in the testes of tammar wallaby pouch young with 5α-pdiol and androsterone as intermediates.[1]

In July 2004, Mala Mahendroo and colleagues described that 3α-diol is the predominant androgen in immature mouse testes, and that it is formed by two pathways; the main one involves testosterone, and a second utilizes the pathway progesterone → 5α-dihydroprogesterone → 5α-pregnane-3α-ol-20-one (allopregnanolone) → 5α-pregnane-3α,17α-diol-20-one (5α-pdiol) → 5α-androstan-3α-ol-17-one (androsterone) → 5α-androstane-3α,17β-diol (3α-diol).[11]

In November 2004, Richard Auchus coined the term "backdoor pathway" in a review called "The backdoor pathway to dihydrotestosterone". He defined the backdoor pathway as a "route to DHT that does not involve the testosterone intermediate". He emphasized that this alternative pathway seems to explain how potent androgens are produced under certain normal and pathological conditions when the conventional androgen biosynthetic pathway cannot fully explain the observed consequences.[2]

Conclusion[edit | edit source]

Androgen backdoor pathway has high clinical significance. Unlike testosterone and androstenedione, androgens produced by the backdoor pathway, i.e. DHT and 11-ketotestosterone, cannot be converted by aromatase into estrogens.[36]

The androgen backdoor pathway is not always considered in the clinical evaluation of patients with hyperandrogenism. If testosterone levels are normal, ignoring the backdoor pathway may lead to diagnostic flaws and confusion, because very potent androgens produced by the backdoor pathway like DHT and 11-ketotestosterone may be the cause of hyperandrogenism.

PubChem IDs[edit | edit source]

In order to unambiguously define all the steroids mentioned in the present review, we give their respective PubChem IDs below. PubChem is a database of molecules, maintained by the National Center for Biotechnology Information of the United States National Institutes of Health. The IDs given below aim to resolve the ambiguity caused by the fact that various authors in describing androgen backdoor pathways used different synonyms for the same metabolic intermediates that do not yet have a commonly agreed canonical names. This practice of unambiguously identifying such substances by their PubChem IDs or IDs from other respectful databases is strongly encouraged.

3α-diol: 15818; 5α-pdiol: 111243; 5α-Dihydroprogesterone: 92810; 5α-Pregnane-3α-ol-20-one: 92786; 11-Ketotestosterone: 104796; 11-Ketoandrosterone: 102029; 11-Ketodihydrotestosterone: 11197479; 11-Deoxycortisol: 440707; 11β-Hydroxyandrostenedione: 94141; 11β-Hydroxyprogesterone: 101788; 17‐OH-DHP: 11889565; 17-OHP: 6238; 21-Deoxycortisol: 92827; Androsterone: 5879; DHT: 10635.

Abbreviations[edit | edit source]

  • 11βOH 11β-hydroxylase
  • 17‐OH-DHP 5α-pregnan-17α-ol-3,20-dione
  • 17-OHP 17α-hydroxyprogesterone
  • 3α-diol 5α-androstane-3α,17β-diol
  • 5α-pdiol 5α-pregnane-3α,17α-diol-20-one
  • Androsterone 5α-androstan-3α-ol-17-one
  • DHT 5α-dihydrotestosterone
  • SRD5A1 3-oxo-5α-steroid 4-dehydrogenase type 1
  • SRD5A2 3-oxo-5α-steroid 4-dehydrogenase type 2

Additional information[edit | edit source]

Competing interests[edit | edit source]

The author have no competing interest.

Acknowledgements[edit | edit source]

Funding[edit | edit source]

Ethics statement[edit | edit source]

References[edit | edit source]

  1. 1.0 1.1 "5alpha-androstane-3alpha,17beta-diol is formed in tammar wallaby pouch young testes by a pathway involving 5alpha-pregnane-3alpha,17alpha-diol-20-one as a key intermediate". Endocrinology 144 (2): 575–80. February 2003. doi:10.1210/en.2002-220721. PMID 12538619. 
  2. 2.0 2.1 2.2 "The backdoor pathway to dihydrotestosterone". Trends in Endocrinology and Metabolism: TEM 15 (9): 432–8. November 2004. doi:10.1016/j.tem.2004.09.004. PMID 15519890. 
  3. 3.0 3.1 "11-Oxygenated Androgens Are Biomarkers of Adrenal Volume and Testicular Adrenal Rest Tumors in 21-Hydroxylase Deficiency". The Journal of Clinical Endocrinology and Metabolism 102 (8): 2701–2710. August 2017. doi:10.1210/jc.2016-3989. PMID 28472487. PMC 5546849. // 
  4. 4.0 4.1 "The Rise, Fall, and Resurrection of 11-Oxygenated Androgens in Human Physiology and Disease". Hormone Research in Paediatrics 89 (5): 284–291. 2018. doi:10.1159/000486036. PMID 29742491. PMC 6031471. 
  5. 5.0 5.1 "The 11β-hydroxysteroid dehydrogenase isoforms: pivotal catalytic activities yield potent C11-oxy C19 steroids with 11βHSD2 favouring 11-ketotestosterone, 11-ketoandrostenedione and 11-ketoprogesterone biosynthesis". The Journal of Steroid Biochemistry and Molecular Biology 189: 116–126. May 2019. doi:10.1016/j.jsbmb.2019.02.013. PMID 30825506. 
  6. 6.0 6.1 "Biochemistry, Dihydrotestosterone".
  7. 7.0 7.1 "Alternative (backdoor) androgen production and masculinization in the human fetus". Plos Biology 17 (2). February 2019. doi:10.1371/journal.pbio.3000002. PMID 30763313. PMC 6375548. // "androsterone as the predominant backdoor androgen in the human fetus" 
  8. 8.0 8.1 "Increased activation of the alternative "backdoor" pathway in patients with 21-hydroxylase deficiency: evidence from urinary steroid hormone analysis". The Journal of Clinical Endocrinology and Metabolism 97 (3). March 2012. doi:10.1210/jc.2011-1997. PMID 22170725. 
  9. 9.0 9.1 "The "backdoor pathway" of androgen synthesis in human male sexual development". PLOS Biology 17 (4). April 2019. doi:10.1371/journal.pbio.3000198. PMID 30943210. PMC 6464227. 
  10. 10.0 10.1 "Prostate formation in a marsupial is mediated by the testicular androgen 5 alpha-androstane-3 alpha,17 beta-diol". Proceedings of the National Academy of Sciences of the United States of America 97 (22): 12256–9. October 2000. doi:10.1073/pnas.220412297. PMID 11035809. PMC 17328. // 
  11. 11.0 11.1 "Steroid 5alpha-reductase 1 promotes 5alpha-androstane-3alpha,17beta-diol synthesis in immature mouse testes by two pathways". Molecular and Cellular Endocrinology 222 (1-2): 113–20. July 2004. doi:10.1016/j.mce.2004.04.009. PMID 15249131. 
  12. "Why boys will be boys: two pathways of fetal testicular androgen biosynthesis are needed for male sexual differentiation". American Journal of Human Genetics 89 (2): 201–18. August 2011. doi:10.1016/j.ajhg.2011.06.009. PMID 21802064. PMC 3155178. // 
  13. 13.0 13.1 13.2 "Alternative pathway androgen biosynthesis and human fetal female virilization". Proceedings of the National Academy of Sciences of the United States of America 116 (44): 22294–22299. October 2019. doi:10.1073/pnas.1906623116. PMID 31611378. PMC 6825302. 
  14. 14.0 14.1 14.2 Pignatelli, Duarte; Pereira, Sofia S.; Pasquali, Renato (2019). "Androgens in Congenital Adrenal Hyperplasia". Hyperandrogenism in Women. Frontiers of Hormone Research. 53. pp. 65–76. doi:10.1159/000494903. ISBN 978-3-318-06470-4. PMID 31499506. 
  15. 15.0 15.1 Sumińska, Marta; Bogusz-Górna, Klaudia; Wegner, Dominika; Fichna, Marta (29 June 2020). "Non-Classic Disorder of Adrenal Steroidogenesis and Clinical Dilemmas in 21-Hydroxylase Deficiency Combined with Backdoor Androgen Pathway. Mini-Review and Case Report". International Journal of Molecular Sciences 21 (13): 4622. doi:10.3390/ijms21134622. PMID 32610579. PMC 7369945. // 
  16. 16.0 16.1 "Backdoor pathway for dihydrotestosterone biosynthesis: implications for normal and abnormal human sex development". Developmental Dynamics 242 (4): 320–9. April 2013. doi:10.1002/dvdy.23892. PMID 23073980. 
  17. 17.0 17.1 Auchus, Richard J. (2010). "Management of the Adult with Congenital Adrenal Hyperplasia". International Journal of Pediatric Endocrinology 2010: 614107. doi:10.1155/2010/614107. PMID 20613954. PMC 2896848. // 
  18. "The role of gonadotropins in testicular and adrenal androgen biosynthesis pathways-Insights from males with congenital hypogonadotropic hypogonadism on hCG/rFSH and on testosterone replacement". Clinical Endocrinology. September 2020. doi:10.1111/cen.14324. PMID 32871622. 
  19. ""Getting from here to there"--mechanisms and limitations to the activation of the androgen receptor in castration-resistant prostate cancer". Journal of Investigative Medicine : the Official Publication of the American Federation for Clinical Research 58 (8): 938–44. December 2010. PMID 21030877. PMC 5589138. // 
  20. "11-Oxygenated androgens in health and disease". Nature Reviews. Endocrinology 16 (5): 284–296. May 2020. doi:10.1038/s41574-020-0336-x. PMID 32203405. 
  21. 21.0 21.1 "The A-ring reduction of 11-ketotestosterone is efficiently catalysed by AKR1D1 and SRD5A2 but not SRD5A1". The Journal of Steroid Biochemistry and Molecular Biology 202: 105724. September 2020. doi:10.1016/j.jsbmb.2020.105724. PMID 32629108. 
  22. "Update on diagnosis and management of congenital adrenal hyperplasia due to 21-hydroxylase deficiency". Current Opinion in Endocrinology, Diabetes, and Obesity 25 (3): 178–184. June 2018. doi:10.1097/MED.0000000000000402. PMID 29718004. 
  23. 23.0 23.1 23.2 "The 11β-hydroxyandrostenedione pathway and C11-oxy C21 backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone". The Journal of Steroid Biochemistry and Molecular Biology 196: 105497. February 2020. doi:10.1016/j.jsbmb.2019.105497. PMID 31626910. 
  24. "Canonical and Noncanonical Androgen Metabolism and Activity". Advances in Experimental Medicine and Biology 1210: 239–277. 2019. doi:10.1007/978-3-030-32656-2_11. PMID 31900912. 
  25. "A high-throughput UPC2-MS/MS method for the separation and quantification of C19 and C21 steroids and their C11-oxy steroid metabolites in the classical, alternative, backdoor and 11OHA4 steroid pathways". Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences 1080: 71–81. March 2018. doi:10.1016/j.jchromb.2018.02.023. PMID 29482121. 
  26. Turcu, A. F.; Rege, J.; Chomic, R.; Liu, J.; Nishimoto, H. K.; Else, T.; Moraitis, A. G.; Palapattu, G. S. et al. (2015). "Profiles of 21-Carbon Steroids in 21-hydroxylase Deficiency". The Journal of Clinical Endocrinology and Metabolism 100 (6): 2283–2290. doi:10.1210/jc.2015-1023. PMID 25850025. PMC 4454804. // 
  27. "MANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and management of the patient with non-classic CAH due to 21-hydroxylase deficiency". European Journal of Endocrinology 180 (3): R127–R145. March 2019. doi:10.1530/EJE-18-0712. PMID 30566904. 
  28. "Adrenal C11-oxy C21 steroids contribute to the C11-oxy C19 steroid pool via the backdoor pathway in the biosynthesis and metabolism of 21-deoxycortisol and 21-deoxycortisone". The Journal of Steroid Biochemistry and Molecular Biology 174: 86–95. November 2017. doi:10.1016/j.jsbmb.2017.07.034. PMID 28774496. 
  29. 29.0 29.1 van Rooyen, Desmaré; Gent, Rachelle; Barnard, Lise; Swart, Amanda C. (April 2018). "The in vitro metabolism of 11β-hydroxyprogesterone and 11-ketoprogesterone to 11-ketodihydrotestosterone in the backdoor pathway". The Journal of Steroid Biochemistry and Molecular Biology 178: 203–212. doi:10.1016/j.jsbmb.2017.12.014. PMID 29277707. 
  30. Gueux, Bernard; Fiet, Jean; Galons, Hervé; Boneté, Rémi; Villette, Jean-Marie; Vexiau, Patrick; Pham-Huu-Trung, Marie-Thérèse; Raux-Eurin, Marie-Charles et al. (January 1987). "The measurement of 11β-hydroxy-4-pregnene-3,20-dione (21-Deoxycorticosterone) by radioimmunoassay in human plasma". Journal of Steroid Biochemistry 26 (1): 145–150. doi:10.1016/0022-4731(87)90043-4. PMID 3546944. 
  31. Fiet, Jean; Gueux, Bernard; Rauxdemay, Marie-Charles; Kuttenn, Frederique; Vexiau, Patrick; Brerault, Jeanlouis; Couillin, Philippe; Galons, Herve et al. (March 1989). "Increased Plasma 21-Deoxycorticosterone (21-DB) Levels in Late-Onset Adrenal 21-Hydroxylase Deficiency Suggest a Mild Defect of the Mineralocorticoid Pathway". The Journal of Clinical Endocrinology & Metabolism 68 (3): 542–547. doi:10.1210/jcem-68-3-542. PMID 2537337. 
  32. Fiet, Jean; Le Bouc, Yves; Guéchot, Jérôme; Hélin, Nicolas; Maubert, Marie-Anne; Farabos, Dominique; Lamazière, Antonin (10 February 2017). "A Liquid Chromatography/Tandem Mass Spectometry Profile of 16 Serum Steroids, Including 21-Deoxycortisol and 21-Deoxycorticosterone, for Management of Congenital Adrenal Hyperplasia". Journal of the Endocrine Society 1 (3): 186–201. doi:10.1210/js.2016-1048. PMID 29264476. PMC 5686660. // 
  33. "CYP17A1 exhibits 17αhydroxylase/17,20-lyase activity towards 11β-hydroxyprogesterone and 11-ketoprogesterone metabolites in the C11-oxy backdoor pathway". The Journal of Steroid Biochemistry and Molecular Biology 199: 105614. May 2020. doi:10.1016/j.jsbmb.2020.105614. PMID 32007561. 
  34. Strushkevich, N.; Gilep, A. A.; Shen, L.; Arrowsmith, C. H.; Edwards, A. M.; Usanov, S. A.; Park, H. W. (2013). "Structural Insights into Aldosterone Synthase Substrate Specificity and Targeted Inhibition". Molecular Endocrinology (Baltimore, Md.) 27 (2): 315–324. doi:10.1210/me.2012-1287. PMID 23322723. PMC 5417327. // 
  35. "Metabolic pathways for 3α-diol formation in immature rat testis microsomes". Biochimica Et Biophysica Acta 924 (1): 1–6. April 1987. doi:10.1016/0304-4165(87)90063-8. PMID 3828389. 
  36. Nagasaki, Keisuke; Takase, Kaoru; Numakura, Chikahiko; Homma, Keiko; Hasegawa, Tomonobu; Fukami, Maki (30 August 2020). "Foetal virilisation caused by overproduction of non-aromatisable 11-oxygenated C19 steroids in maternal adrenal tumour". Human Reproduction. doi:10.1093/humrep/deaa221. PMID 32862221.