Glucocorticoids are induced while dihydrotestosterone levels are suppressed in 5-alpha reductase inhibitor treated human benign prostate hyperplasia patients.
3-Oxo-5-alpha-Steroid 4-Dehydrogenase
5-alpha Reductase Inhibitors
/ pharmacology
Dihydrotestosterone
/ metabolism
Glucocorticoids
/ metabolism
Humans
Hyperplasia
/ metabolism
Lower Urinary Tract Symptoms
/ pathology
Male
Membrane Proteins
/ metabolism
Prostate
/ pathology
Prostatic Hyperplasia
/ genetics
BPH
LUTS
androgen
glucocorticoid
prostate branching
prostate hyperplasia
Journal
The Prostate
ISSN: 1097-0045
Titre abrégé: Prostate
Pays: United States
ID NLM: 8101368
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
revised:
10
05
2022
received:
28
02
2022
accepted:
24
06
2022
pubmed:
14
7
2022
medline:
1
9
2022
entrez:
13
7
2022
Statut:
ppublish
Résumé
The development of benign prostatic hyperplasia (BPH) and medication-refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS. Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching. BPH patients on 5-α-reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone (DHT), increased levels of steroid 5-α-reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate-specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha-adrenergic receptor antagonists (α-blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching. After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI-induced pathway increased tissue levels of GC not seen in patients on α-blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI-induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth.
Sections du résumé
BACKGROUND
The development of benign prostatic hyperplasia (BPH) and medication-refractory lower urinary tract symptoms (LUTS) remain poorly understood. This study attempted to characterize the pathways associated with failure of medical therapy for BPH/LUTS.
METHODS
Transitional zone tissue levels of cholesterol and steroids were measured in patients who failed medical therapy for BPH/LUTS and controls. Prostatic gene expression was measured using qPCR and BPH cells were used in organoid culture to study prostatic branching.
RESULTS
BPH patients on 5-α-reductase inhibitor (5ARI) showed low levels of tissue dihydrotestosterone (DHT), increased levels of steroid 5-α-reductase type II (SRD5A2), and diminished levels of androgen receptor (AR) target genes, prostate-specific antigen (PSA), and transmembrane serine protease 2 (TMPRSS2). 5ARI raised prostatic tissue levels of glucocorticoids (GC), whereas alpha-adrenergic receptor antagonists (α-blockers) did not. Nuclear localization of GR in prostatic epithelium and stroma appeared in all patient samples. Treatment of four BPH organoid cell lines with dexamethasone, a synthetic GC, resulted in budding and branching.
CONCLUSIONS
After failure of medical therapy for BPH/LUTS, 5ARI therapy continued to inhibit androgenesis but a 5ARI-induced pathway increased tissue levels of GC not seen in patients on α-blockers. GC stimulation of organoids indicated that the GC receptors are a trigger for controlling growth of prostate glands. A 5ARI-induced pathway revealed GC activation can serve as a master regulator of prostatic branching and growth.
Identifiants
pubmed: 35821619
doi: 10.1002/pros.24410
pmc: PMC9427722
mid: NIHMS1820618
doi:
Substances chimiques
5-alpha Reductase Inhibitors
0
Glucocorticoids
0
Membrane Proteins
0
Dihydrotestosterone
08J2K08A3Y
3-Oxo-5-alpha-Steroid 4-Dehydrogenase
EC 1.3.99.5
SRD5A2 protein, human
EC 1.3.99.5
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1378-1388Subventions
Organisme : NCI NIH HHS
ID : P30 CA016056
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK111554
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK115477
Pays : United States
Informations de copyright
© 2022 Wiley Periodicals LLC.
Références
Nat Commun. 2016 Aug 02;7:12309
pubmed: 27480037
Endocrinology. 2016 Mar;157(3):1094-109
pubmed: 26677878
Endocrinology. 2015 Aug;156(8):2863-71
pubmed: 25974403
Prostate. 2014 May;74(7):722-31
pubmed: 24847527
Eur Urol. 2010 Jan;57(1):123-31
pubmed: 19825505
Prostate Cancer Prostatic Dis. 2012 Sep;15(3):222-30
pubmed: 22333687
Am J Pathol. 2001 Jul;159(1):139-47
pubmed: 11438462
Prostate. 1986;8(1):51-61
pubmed: 2418431
Prostate. 2013 Jun;73(8):884-96
pubmed: 23280591
Genes Immun. 2012 Oct;13(7):566-72
pubmed: 22952051
Breast Cancer Res. 2006;8(1):201
pubmed: 16524451
Urology. 2009 May;73(5):935-9
pubmed: 19328538
Prostate Int. 2014 Sep;2(3):105-13
pubmed: 25325021
J Clin Endocrinol Metab. 2020 Sep 1;105(9):
pubmed: 32594135
Horm Mol Biol Clin Investig. 2017 Jun 21;30(3):
pubmed: 28632494
BMC Genomics. 2014 Mar 25;15:231
pubmed: 24661679
J Urol. 2012 Oct;188(4):1375-81
pubmed: 22906651
Dev Biol. 2003 Dec 15;264(2):352-62
pubmed: 14651923
Am J Pathol. 2013 Feb;182(2):449-59
pubmed: 23219716
Control Clin Trials. 2003 Apr;24(2):224-43
pubmed: 12689743
J Urol. 2016 Nov;196(5):1493-1498
pubmed: 27378134
J Urol. 2011 Apr;185(4):1369-73
pubmed: 21334655
Endocrinology. 2021 Sep 1;162(9):
pubmed: 34180973
Urology. 2013 May;81(5):1018-23
pubmed: 23608423
Dev Biol. 1988 Jul;128(1):1-14
pubmed: 3384172
Nature. 1995 Feb 2;373(6513):427-32
pubmed: 7830793
Mol Endocrinol. 2014 Jun;28(6):949-64
pubmed: 24801505
Dev Biol. 2005 Dec 15;288(2):334-47
pubmed: 16324690
Differentiation. 2011 Nov-Dec;82(4-5):220-36
pubmed: 21645960
Prostate. 2016 Apr;76(5):491-511
pubmed: 26709083
Annu Rev Biochem. 1994;63:25-61
pubmed: 7979239
N Engl J Med. 2013 Aug 15;369(7):603-10
pubmed: 23944298
J Urol. 2015 Aug;194(2):454-61
pubmed: 25828974
Mol Cell Endocrinol. 2019 Apr 15;486:79-88
pubmed: 30807787
Prostate. 2021 Sep;81(13):944-955
pubmed: 34288015
Prostate. 2013 Sep;73(13):1470-82
pubmed: 23813697
Prostate. 2011 Feb 15;71(3):289-97
pubmed: 20717994
N Engl J Med. 2003 Dec 18;349(25):2387-98
pubmed: 14681504
Prostate. 2016 Aug;76(11):1004-18
pubmed: 27197599
Prostate. 2014 May;74(6):669-79
pubmed: 24500928
N Engl J Med. 2003 Jul 17;349(3):215-24
pubmed: 12824459
Cell. 2013 Dec 5;155(6):1309-22
pubmed: 24315100
J Urol. 2004 Feb;171(2 Pt 2):S30-4; discussion S35
pubmed: 14713750
Clin Cancer Res. 2005 Jul 1;11(13):4653-7
pubmed: 16000557
Nat Commun. 2020 Apr 24;11(1):1987
pubmed: 32332823