Editing Benign prostatic hyperplasia (section)

=== Hormones ===
Most experts consider [[androgen]]s ([[testosterone]] and related [[hormone]]s) to play a permissive role in the development of BPH. This means that androgens must be present for BPH to occur, but do not necessarily directly cause the condition. This is supported by evidence suggesting that [[castration|castrated]] boys do not develop BPH when they age. In a study of 26 [[eunuch]]s from the palace of the [[Qing dynasty]] still living in [[Beijing]] in 1960, the prostate could not be felt in 81% of the studied eunuchs.<ref>{{cite journal | vauthors = Wu CP, Gu FL | title = The prostate in eunuchs | journal = Progress in Clinical and Biological Research | volume = 370 | pages = 249–255 | date = 1991 | pmid = 1924456 }}</ref> The average time since castration was 54 years (range, 41–65 years). On the other hand, some studies suggest that administering exogenous testosterone is not associated with a significant increase in the risk of BPH symptoms, so the role of testosterone in prostate cancer and BPH is still unclear. Further randomized controlled trials with more participants are needed to quantify any risk of giving exogenous testosterone.<ref>{{cite web |title = Testosterone and Aging: Clinical Research Directions. |url = https://www.ncbi.nlm.nih.gov/books/NBK216175/ |publisher = NCBI Bookshelf |access-date = 2 February 2015 |url-status = live |archive-url = https://web.archive.org/web/20171105194336/https://www.ncbi.nlm.nih.gov/books/NBK216175/ |archive-date = 5 November 2017}}</ref>

[[Dihydrotestosterone]] (DHT), a [[metabolite]] of testosterone, is a critical mediator of prostatic growth. DHT is synthesized in the prostate from circulating testosterone by the action of the [[enzyme]] [[5α-reductase]], type 2. DHT can act in an [[autocrine]] fashion on the stromal cells or in [[paracrine]] fashion by diffusing into nearby [[epithelium|epithelial cells]]. In both of these cell types, DHT binds to nuclear [[androgen receptor]]s and signals the [[Transcription (genetics)|transcription]] of [[growth factor]]s that are mitogenic to the epithelial and stromal cells. DHT is ten times more potent than testosterone because it dissociates from the androgen receptor more slowly. The importance of DHT in causing [[nodule (medicine)|nodular]] hyperplasia is supported by clinical observations in which an [[Enzyme inhibitor|inhibitor]] of 5α-reductase such as [[finasteride]] is given to men with this condition. Therapy with a 5α-reductase inhibitor markedly reduces the DHT content of the prostate and, in turn, reduces prostate volume and BPH symptoms.<ref>{{cite web |title = Proscar (finasteride) Prescribing Information |url = http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020180s037lbl.pdf |website = FDA – Drug Documents |publisher = Merck and Company |access-date = 2 March 2015 |url-status = live |archive-url = https://web.archive.org/web/20160303231752/http://www.accessdata.fda.gov/drugsatfda_docs/label/2010/020180s037lbl.pdf |archive-date = 3 March 2016}}</ref><ref>{{cite journal | vauthors = Bartsch G, Rittmaster RS, Klocker H | title = Dihydrotestosterone and the concept of 5alpha-reductase inhibition in human benign prostatic hyperplasia | journal = World Journal of Urology | volume = 19 | issue = 6 | pages = 413–425 | date = April 2002 | pmid = 12022710 | doi = 10.1007/s00345-002-0248-5 | s2cid = 3257666 }}</ref>

Testosterone promotes prostate cell proliferation,<ref name="Feldman2001">{{cite journal | vauthors = Feldman BJ, Feldman D | title = The development of androgen-independent prostate cancer | journal = Nature Reviews. Cancer | volume = 1 | issue = 1 | pages = 34–45 | date = October 2001 | pmid = 11900250 | doi = 10.1038/35094009 | s2cid = 205020623 }}</ref> but relatively low levels of serum testosterone are found in patients with BPH.<ref name="Lagiou1997">{{cite journal | vauthors = Lagiou P, Mantzoros CS, Tzonou A, Signorello LB, Lipworth L, Trichopoulos D | title = Serum steroids in relation to benign prostatic hyperplasia | journal = Oncology | volume = 54 | issue = 6 | pages = 497–501 | year = 1997 | pmid = 9394847 | doi = 10.1159/000227609 }}</ref><ref name="Roberts2004">{{cite journal | vauthors = Roberts RO, Jacobson DJ, Rhodes T, Klee GG, Leiber MM, Jacobsen SJ | title = Serum sex hormones and measures of benign prostatic hyperplasia | journal = The Prostate | volume = 61 | issue = 2 | pages = 124–131 | date = October 2004 | pmid = 15305335 | doi = 10.1002/pros.20080 | s2cid = 24288565 }}</ref> One small study has shown that medical castration lowers the serum and prostate hormone levels unevenly, having less effect on testosterone and dihydrotestosterone levels in the prostate.<ref name="Page2006">{{cite journal | vauthors = Page ST, Lin DW, Mostaghel EA, Hess DL, True LD, Amory JK, Nelson PS, Matsumoto AM, Bremner WJ | title = Persistent intraprostatic androgen concentrations after medical castration in healthy men | journal = The Journal of Clinical Endocrinology and Metabolism | volume = 91 | issue = 10 | pages = 3850–3856 | date = October 2006 | pmid = 16882745 | doi = 10.1210/jc.2006-0968 | doi-access = free }}</ref>

Besides testosterone and DHT, other androgens are also known to play a crucial role in BPH development. {{chem|C|21}} 11-oxygenated steroids (pregnanes) have been identified are precursors to 11-oxygenated androgens which are also potent agonists for the androgen receptor.<ref name="pmid18308097">{{cite journal | vauthors = Dimitrakov J, Joffe HV, Soldin SJ, Bolus R, Buffington CA, Nickel JC | title = Adrenocortical hormone abnormalities in men with chronic prostatitis/chronic pelvic pain syndrome | journal = Urology | volume = 71 | issue = 2 | pages = 261–266 | date = February 2008 | pmid = 18308097 | pmc = 2390769 | doi = 10.1016/j.urology.2007.09.025 }}</ref> Specifically, steroids like [[11β-hydroxyprogesterone]] and [[11-ketoprogesterone]] can be converted to [[11-ketodihydrotestosterone]], an 11-oxo form of DHT with the same potency. These precursors have also been detected in tissue [[biopsy]] samples from patients with BPH, as well as in their serum levels.<ref name="pmid31626910">{{cite journal | vauthors = du Toit T, Swart AC | title = The 11β-hydroxyandrostenedione pathway and C11-oxy C<sub>21</sub> backdoor pathway are active in benign prostatic hyperplasia yielding 11keto-testosterone and 11keto-progesterone | journal = The Journal of Steroid Biochemistry and Molecular Biology | volume = 196 | pages = 105497 | date = February 2020 | pmid = 31626910 | doi = 10.1016/j.jsbmb.2019.105497 | s2cid = 204734045 }}</ref><ref name="pmid35987379">{{cite journal | vauthors = Masiutin MG, Yadav MK | title = "Re: Adrenocortical Hormone Abnormalities in Men With Chronic Prostatitis/Chronic Pelvic Pain Syndrome" | language = English | journal = Urology | volume = 169 | pages = 273 | date = November 2022 | pmid = 35987379 | doi = 10.1016/j.urology.2022.07.051 | s2cid = 251657694 }}</ref><ref name="pmid35985522">{{cite journal | vauthors = Dimitrakoff J, Nickel JC | title = Author Reply | language = English | journal = Urology | volume = 169 | pages = 273–274 | date = November 2022 | pmid = 35985522 | doi = 10.1016/j.urology.2022.07.049 | s2cid = 251658492 }}</ref> Besides that, androgens biosynthesized via a [[androgen backdoor pathway|backdoor pathway]] can contribute to the development of BPH.<ref name="pmid31626910"/>

While there is some evidence that estrogen may play a role in the cause of BPH, this effect appears to be mediated mainly through local conversion of androgens to estrogen in the prostate tissue rather than a direct effect of estrogen itself.<ref name="Ho2008">{{cite journal | vauthors = Ho CK, Nanda J, Chapman KE, Habib FK | title = Oestrogen and benign prostatic hyperplasia: effects on stromal cell proliferation and local formation from androgen | journal = The Journal of Endocrinology | volume = 197 | issue = 3 | pages = 483–491 | date = June 2008 | pmid = 18492814 | doi = 10.1677/JOE-07-0470 | doi-access = free }}</ref> In canine ''in vivo'' studies castration, which significantly reduced androgen levels but left estrogen levels unchanged, caused significant atrophy of the prostate.<ref name="Niu2003">{{cite journal | vauthors = Niu YJ, Ma TX, Zhang J, Xu Y, Han RF, Sun G | title = Androgen and prostatic stroma | journal = Asian Journal of Andrology | volume = 5 | issue = 1 | pages = 19–26 | date = March 2003 | pmid = 12646998 }}</ref> Studies looking for a correlation between prostatic hyperplasia and serum estrogen levels in humans have generally shown none.<ref name="Roberts2004" /><ref name="Ansari2008">{{cite journal | vauthors = Ansari MA, Begum D, Islam F | title = Serum sex steroids, gonadotrophins and sex hormone-binding globulin in prostatic hyperplasia | journal = Annals of Saudi Medicine | volume = 28 | issue = 3 | pages = 174–178 | year = 2008 | pmid = 18500180 | pmc = 6074428 | doi = 10.4103/0256-4947.51727 | doi-access = free }}</ref>

In 2008, Gat et al. published evidence that BPH is caused by failure in the spermatic venous drainage system resulting in increased hydrostatic pressure and local testosterone levels elevated more than 100-fold above serum levels.<ref name="pmid18811916">{{cite journal | vauthors = Gat Y, Gornish M, Heiblum M, Joshua S | title = Reversal of benign prostate hyperplasia by selective occlusion of impaired venous drainage in the male reproductive system: novel mechanism, new treatment | journal = Andrologia | volume = 40 | issue = 5 | pages = 273–281 | date = October 2008 | pmid = 18811916 | doi = 10.1111/j.1439-0272.2008.00883.x | s2cid = 205442245 | doi-access = free }}</ref> If confirmed, this mechanism explains why serum androgen levels do not seem to correlate with BPH and why giving exogenous testosterone would not make much difference.