Testosterone, Urethral Vascularity, Thiab Urethral Stricture Disease: Kev Ntsuam Xyuas

Abstract

Cov kab mob urethral stricture yog ib qho ntawm cov laus tshaj plaws piav txog pathologies urologic thiab urethroplasty yog txuam nrog kev ua tau zoo. Ntau qhov urethral nruj yog xav tias yuav tshwm sim los ntawm iatrogenic raug mob los yog kev kho hluav taws xob uas tuaj yeem tsim kev thuam rau cov urethra. Hauv cov teb chaws tsim kho, feem ntau cov urethral strictures yog idiopathic; yog li ntawd, ntau yam tseem tsis tau paub txog etiology thiab pathogenesis ntawm tus kab mob no. Testosterone paub los kho vasculogenesis los ntawm vascular endothelial kev loj hlob yam (VEGF) thiab hypoxia-inducible factor-1 (HIF-1) txoj hauv kev hauv ntau yam kabmob.

Nyem rau cistanche herba rau mob raum

Tsis ntev los no, Testosterone tau pom los kho cov kab mob urethral vasculogenesis. Hauv kev teeb tsa ntawm testosterone tsis txaus, androgen supplementation tuaj yeem txhim kho urethral vascularity. Tsis tas li ntawd, zoo li muaj qhov tshwm sim siab ntawm testosterone deficiency hauv cov txiv neej uas muaj cov urethral nruj. Txawm hais tias muaj ntau qhov kev nce qib hauv peb txoj kev nkag siab ntawm testosterone lub koom haum nrog cov urethra ob peb xyoos dhau los, tseem muaj ntau yam yuav tsum tau kawm txog cov txheej txheem ntawm testosterone ntawm cov urethral stricture etiology thiab seb testosterone deficiency thiab supplementation cuam tshuam rau urethral reconstruction.

1 Kev Taw Qhia

Cov kab mob urethral stricture tau piav qhia thaum ntxov li xyoo pua BC hauv Is Nrias teb thaum ub thiab tau kho nrog dilation los ntawm lub reed catheter thaum lub sij hawm ntawd [1]. Txawm hais tias nws yog ib qho ntawm cov laus tshaj plaws piav qhia pathologies hauv urology thiab tshuaj, etiology tseem tsis tau nkag siab zoo hauv ntau tus neeg mob. Cov feem ntau etiologies rau anterior urethral strictures yog iatrogenic, kis, raug mob, thiab lichen sclerosis (LS) kab mob (yav tas los hu ua balanitis xerotica obliterans). Hauv cov teb chaws tsim, ib qho idiopathic lossis tsis paub etiology suav rau 34 feem pua ​​-41 feem pua ​​​​ntawm cov kab mob hauv lub urethral strictures [2–5].

Qee qhov idiopathic strictures tej zaum yuav tshwm sim los ntawm unrecognized perineal raug mob; Txawm li cas los, ib tug ntau tseem tsis to taub txog lub etiology ntawm ntau strictures. Iatrogenic strictures feem ntau yog tshwm sim los ntawm transurethral instrumentation / catheterization, hypospadias phais, los yog kev kho mob qog noj ntshav prostate. Cov kev thuam no feem ntau ua rau muaj kev raug mob ischemic rau lub urethra ua rau muaj kev nruj nruj. Angiogenesis mediates kho qhov txhab tom qab kev thuam ntawm ischemic. Ntau tus qauv tau pom lub luag haujlwm ntawm androgens hauv kev tswj hwm ntawm ischemia-induced angiogenesis [6,7]. Androgens tau pom tias yuav hloov kho angiogenesis los ntawm vascular endothelial kev loj hlob yam (VEGF) thiab hypoxia-inducible factor-1 (HIF-1) txoj kev [7].

Hauv cov qauv tsiaj, testosterone deficiency (TD) impairs cytokine qhia thiab homing ntawm qia hlwb uas induce neovascularization nyob rau hauv lub plawv cov ntaub so ntswg tom qab ischemic puas los ntawm myocardial infarction [8]. Tsis tas li ntawd, nws tau pom tias kev hloov pauv testosterone tuaj yeem rov qab kho neovascularization hauv TD nas [8]. Kev sib deev cov tshuaj hormones tau ntev tau txiav txim siab nyob rau hauv pathogenesis thiab kev kho mob ntawm cov kab mob urethral, ​​uas yog hypospadias. Kev raug tshuaj estrogen tau pom tias ua rau raug ntes urethral txoj kev loj hlob.

Xwb, testosterone raug rau txiv neej nas nyob rau hauv utero ua rau muaj zog peri-urethral spongiosis cov ntaub so ntswg [9]. Androgen stimulation ua ntej hypospadias phais yog thawj zaug siv nyob rau hauv 1971 [10]. Preoperative Testosterone muaj ntau qhov zoo theoretical nrog rau kev nce noov thiab glandular loj ntxiv nrog rau kev nce hauv preputial vascularity [11-15]. Raws li txoj cai, kev txhim kho cov ntaub so ntswg zoo thiab vascularity yuav ua rau lub qhov txhab zoo dua qub thiab cov txiaj ntsig.

Cov txiaj ntsig ntawm hormonal stimulation ntawm hypospadias cov txiaj ntsig tau tsis sib haum xeeb [16,17] thiab kev siv cov tshuaj testosterone ua ntej tseem muaj teeb meem. Raws li kev nkag siab ntawm lub luag haujlwm ntawm testosterone hauv urethral txoj kev loj hlob thiab angiogenesis tau loj hlob, nws tau ua rau muaj kev txaus siab tshaj li hypospadias thiab mus rau lwm yam kab mob hauv lub urethral nrog rau cov kab mob urethral stricture.

Lub hom phiaj ntawm qhov kev tshuaj xyuas no yog los tham txog lub luag haujlwm ntawm (1) testosterone hauv urethral vascularity, (2) TD thiab urethral stricture disease, (3) testosterone supplementation on urethral vascularity, and (4) future directions of testosterone and stricture disease.

2. Testosterone thiab AUS Urethral Erosion

Ntau xyoo dhau los no tau muaj kev txaus siab rau testosterone thiab cov neeg laus urethral pathologies. Thawj cov koob uas txhawb nqa qhov kev txaus siab no tau soj ntsuam testosterone thiab urethral yaig tom qab kev tso zis urinary sphincter (AUS) [18]. Cov kws sau ntawv tau pom tias muaj kev nce hauv AUS erosions hauv cov txiv neej nrog TD. Hauv daim ntawv no, Hofer et al. [18] soj ntsuam cov qib ntshav testosterone hauv 53 cov neeg mob sib law liag uas tau nthuav tawm rau kev soj ntsuam tom qab AUS tso.

Lawv txhais TD li<280 ng/dL. Twenty patients had an AUS erosion, of which 18 (90%) had TD [18]. Only 9% of men with normal serum testosterone had an erosion. In a multivariate analysis, TD was independently associated with AUS erosion [18]. Interestingly, on multivariate analysis, radiation was not associated with AUS erosion although a higher number of patients with erosion had prior radiation therapy (80% vs 51%, p = 0.038) [18]. The same group performed a larger retrospective review of all patients who underwent AUS by a single surgeon [19]. 

Lawv tau txheeb xyuas 161 tus txiv neej uas tau nkag mus rau AUS thiab muaj cov qib testosterone qib perioperative. Testosterone qib qis hauv cov neeg mob uas muaj urethral yaig. Cov txiv neej nrog TD muaj feem ntau yuav muaj urethral yaig (los yog 2.519, p=0.021). Ib zaug ntxiv, ntawm lawv cov kev txheeb xyuas ntau yam, TD yog tib yam cuam tshuam nrog urethral yaig [19].

Ua ntej pelvic radiation therapy, AUS phais, thiab ua ntej urethral reconstruction yog paub txog cov kev pheej hmoo ntawm AUS urethral erosion [20-22], thiab tag nrho cov cuam tshuam periurethral vascularity. Kev kho hluav taws xob ua rau obliterative endarteritis, thiab ua ntej urethral dissection tso cov urethra ntawm kev pheej hmoo ntawm ib feem ntawm kev puas tsuaj thiab atrophy [18]. Kev cuam tshuam rau urethral vascularity tshwm sim ua rau muaj kev pheej hmoo ntawm urethral sub-cuff atrophy thiab yaig.

Txij li thaum testosterone paub txog kev kho mob angiogenesis, qhov haujlwm no tau txhawb kev tshawb nrhiav ntxiv txog testosterone qhov cuam tshuam rau cov hlab ntsha hauv urethral [18].

3. Testosterone thiab Urethral Vascularity

Ua raws li qhov kev tshawb pom los ntawm Hofer et al. [18] nyob rau hauv 2016, tib pab pawg tau tshawb nrhiav androgen-mediated vascularity nyob rau hauv cov txiv neej nrog ib txwm thiab tsis tshua muaj ntshav siab testosterone qib. Lawv piv androgen receptor (AR) qhia, nws downstream phiaj lub angiopoietin -1 receptor (TIE-2), thiab tag nrho cov vascularity los yog hlab ntsha suav nyob rau hauv urethral stricture ntaub so ntswg ntawm cov txiv neej uas underwent urethroplasty. Cov pab pawg muaj xws li 11 tus txiv neej uas muaj qib testosterone qib hauv 2 xyoos ntawm urethroplasty.

Lawv pom qhov txo qis ntawm AR (1.11 feem pua ​​​​siab zog [HPF] vs 1.62, p=0.016), TIE-2 (1.84 feem pua ​​HPF vs 3.08, p=0.006) , thiab tag nrho cov hlab ntsha suav (44.47 hlab ntsha/HPF vs 98.33, p=0.004) hauv cov txiv neej uas muaj cov ntshav testosterone tsawg dua 280 ng/dL. Lawv kuj tau sau tseg qhov tsis tseem ceeb ntawm kev sib raug zoo ntawm cov hlab ntsha suav thiab cov ntshav testosterone [23].

Txoj kev tshawb no muaj ib pawg neeg xaiv ntau heev ntawm cov neeg mob. Thaum lub sijhawm kawm, kwv yees li 1200 tus neeg mob tau txais kev kho mob urethroplasty ntawm lub tsev kawm ntawv no, tab sis tsuas yog 11 tau ntsib cov txheej txheem suav nrog cov qib testosterone qib perioperative uas yeej qhia txog qib kev xaiv tsis zoo. Txawm hais tias muaj kev txwv ntawm tsab xov xwm no, cov kws sau ntawv qhia txog cov qauv kev ua haujlwm ntawm cov tshuaj testosterone tsawg ntawm cov urethral thiab corpus spongiosum vasculogenesis tswj los ntawm AR thiab TIE-2 receptors [23].

AR-mediated vasculogenesis yog qhov nyuaj thiab muaj feem ntau yuav muaj feem cuam tshuam rau hauv cov txheej txheem no nyob rau hauv cov ntaub so ntswg urethral thiab periurethral xws li VEGF lossis HIF1; txawm li cas los xij, tsis muaj ntaub ntawv rau hnub no tau tshawb xyuas lub luag haujlwm ntawm cov txheej txheem no. Levy et al. [24] tshawb nrhiav cov cim kab mob hauv cov kab mob urethral nruj ntawm LS thiab cov neeg mob uas tsis yog LS.

Cov kws sau ntawv lub hom phiaj yog los soj ntsuam cov kab mob pathophysiology ntawm LS nruj los ntawm kev tshuaj xyuas cov protein qhia ntsig txog kev mob, kev cuam tshuam ntawm lub voj voog ntawm tes, oxidative kev nyuaj siab, cov tshuaj hormone receptor, thiab kev kis kab mob. Kev lees paub, lub hom phiaj ntawm daim ntawv no tsis yog los tshawb txog androgen tshwj xeeb cuam tshuam rau cov urethral strictures. Lawv tau tshuaj xyuas cov ntaub so ntswg los ntawm 81 qhov urethral strictures thiab pom poob ntawm AR nyob rau hauv 43 feem pua ​​​​ntawm tag nrho cov strictures.

Tsis muaj qhov sib txawv ntawm LS thiab tsis yog LS nruj. Interestingly, lawv kuj pom tias ze li ob feem peb ntawm cov kev nruj me ntsis qhia cov qib siab ntawm VEGF [24]. Cov koob no tsis tau txheeb xyuas cov qib testosterone hauv cov ntshav thiab yog li cov lus xaus hais txog qhov cuam tshuam ntawm cov ntshav ntshav testosterone ntawm AR thiab VEGF tsis tuaj yeem rub los ntawm cov koob no. Txawm li cas los xij, cov txiaj ntsig tau nthuav dav thiab ntxiv rau kev ua haujlwm los ntawm Hofer li al. [23] Qhia txog kev hloov pauv hauv kev qhia ntawm AR hauv cov kab mob urethral nruj.

4. Testosterone Deficiency thiab Urethral Stricture Disease

Spencer et al. [25] tau ua qhov kev tshuaj xyuas rov qab ntawm cov neeg mob uas tau txais urethroplasty los ntawm ob tus kws phais hauv ob lub tsev kho mob. Kev ntsuam xyuas ua ntej testosterone yog ib feem ntawm kev coj ua ntawm ob tus kws phais. Lawv tsis suav nrog cov neeg mob uas muaj keeb kwm ntawm pelvic radiation, prostatectomy, lossis pelvic fracture urethral raug mob.

Zuag qhia tag nrho 157/202 tau ntsib cov txheej txheem suav nrog uas 115 muaj testosterone ua ntej. Cov kws sau ntawv no pom 56.5 feem pua ​​​​ntawm cov txiv neej uas tab tom ua urethroplasty muaj TD raws li txhais los ntawm cov ntshav testosterone.<300 ng/dL. BMI was associated with low testosterone levels (p < 0.00001). They compared this group to the National Health and Nutrition Examination Survey (NHANES) database. During 2011–2012 all males in the NHANES dataset had testosterone levels assessed and men >18 xyoo tau suav nrog pawg sib piv.

Pab pawg NHANES muaj 2575 tus txiv neej rau kev tshuaj xyuas uas 28 feem pua ​​​​tau muaj cov tshuaj testosterone<300 ng/dL [25]. The authors then analyzed stricture characteristics among men with low and normal testosterone levels. Men with low testosterone levels had higher BMI, 36 kg/m2 vs 29 kg/m2 (p < 0.00001). In men with low serum testosterone, stricture length was significantly longer than in the normal testosterone group, 7.2 cm vs 4.8 cm (p = 0.02). They found no difference in stricture etiology between groups with normal and low serum testosterone. On multivariate analysis, TD remained associated with stricture length (p = 0.015) [25]. 

Txawm hais tias muaj kev txwv pom tseeb ntawm kev siv lub teb chaws cov ntaub ntawv raws li pab pawg sib piv thiab kev xaiv kev tsis ncaj ncees cuam tshuam nrog kev tsim rov qab, txoj kev tshawb no qhia tias cov txiv neej uas muaj kab mob urethral stricture muaj qhov tshwm sim ntau dua ntawm cov tshuaj testosterone tsawg. Tsis tas li ntawd, cov lus nug txog kev ua haujlwm no seb TD puas muaj lub luag haujlwm hauv cov kab mob ntawm cov kab mob urethral strictures ua rau muaj kab mob hnyav dua li TD tau cuam tshuam nrog qhov ntev. Bonilla et al. [26] tsis ntev los no tau luam tawm ib qho kev paub daws teeb meem los ntawm kev tshawb nrhiav cov ntaub ntawv sib txuas ntawm cov txiv neej uas nthuav tawm rau ib lub koom haum ntsuas TD hauv cov txiv neej uas muaj kab mob urethral nruj. Lawv tau sib piv cov qib testosterone qib hauv cov txiv neej uas nthuav tawm rau kev ntsuam xyuas urethral nruj rau cov txiv neej uas qhia txog qhov tsis txaus siab txog kev tsis txaus siab.

Lawv muaj 120 cov txiv neej nrog urethral nruj thiab 41 tswj. Tsis muaj qhov sib txawv ntawm cov pej xeem lossis kev sib txawv ntawm cov pab pawg. Lub ntsiab lus ntawm testosterone qib tau qis dua (391 ng / dL vs 495 ng / dL, p < 0.01) hauv cov txiv neej uas muaj cov urethral strictures txawm hais tias qhov nruab nrab yog siab dua 300 ng / dL hauv ob pawg.

Cov txiv neej uas muaj kab mob urethral stricture kuj muaj ntau dua cov tshuaj follicle-stimulating hormone (10.7 mIU/mL vs 5.{11}}1 mIU/mL, p < 0.01) thiab luteinizing hormone (6.2 mIU / mL vs 4.2 mIU/mL, p <0.01). Serum testosterone yog<300 ng/dL in significantly more men with urethral stricture disease (35.8% vs 14.6%, p < 0.007; OR 3.2, CI 1.27–8.33) [26]. These studies taken together demonstrate a growing body of evidence that TD is more common in men with urethral stricture disease. It is still, however, unclear if serum testosterone has a role in stricture pathogenesis.

5. Testosterone Supplementation thiab Urethral Vascularity

Raws li cov ntaub ntawv pov thawj txhawb kev sib txuas ntawm cov ntshav qis testosterone thiab cov hlab ntsha hauv cov hlab ntsha loj hlob tuaj, kev siv zog tau hloov mus rau kev txiav txim siab seb qhov urethral vascularity tuaj yeem txhim kho nrog cov tshuaj hormones ntxiv. Yura thiab cov npoj yaig [27] thawj zaug ntsuas qhov no hauv tus qauv nas. Lawv faib 24 Sprague Dawley nas rau hauv plaub pawg: kev tswj tsis yog castrate, castrate, castrate nrog testosterone supplementation, thiab castrate nrog estrogen supplementation. Lawv piv AR, TIE-2, thiab CD31 qhia ntawm pawg. CD31 yog ib qho rhiab heev rau cov ntaub so ntswg. CD31 tau txo qis hauv cov nas castrated piv rau cov tswj.

AR thiab TIE-2 tsis pom nyob rau hauv pawg castrated. Tom qab supplementation nrog testosterone tag nrho cov hlab ntsha suav, AR, thiab TIE-2 qhia tau nce ntau. Testosterone rov qab CD31 thiab AR qhia mus rau qib siab dua li pawg tswj tsis-castrate [27]. Estrogen supplementation txhim kho CD31 tab sis tsis yog AR lossis TIE-2 qhia [27]. Cov kev tshawb pom no qhia tau hais tias testosterone supplementation restores periurethral vascularity hauv tus qauv tsiaj.

Tib pab pawg tom qab ntawd tau soj ntsuam qhov cuam tshuam ntawm cov tshuaj hormones ntxiv rau cov ntaub so ntswg urethral tom qab urethroplasty hauv tus qauv nas [28]. Lawv faib 48 nas rau tib pab pawg (tsis yog-castrate tswj, castrate, castrate nrog testosterone supplementation, thiab castrate nrog estrogen supplementation). Hauv txhua pab pawg ib nrab ntawm cov nas tau txais Heineke Mikulicz-style urethroplasty. CD31 qhia tau siv los ntsuas cov ntaub so ntswg vascular thiab nws tau nce tom qab kev ua haujlwm hauv pawg tswj hwm nrog rau testosterone thiab estrogen caj npab piv rau caj npab castrate. AR qhia tau qis me ntsis hauv cov uas tau txais kev phais piv rau tsis muaj kev phais hauv caj npab ntxiv testosterone (5.21 feem pua ​​​​vs 4.24 feem pua ​​, p=0.042).

TIE{{0}}} kev qhia tau nce hauv ob qho kev tswj hwm (0.43 feem pua ​​vs 0.85 feem pua ​​, p=0.0{{ 11}}1) thiab testosterone supplementation cohort (0.20 feem pua ​​vs 0.70 feem pua ​​, p <0.001) tom qab urethroplasty. Tom qab ntawd lawv pom CD31 muaj feem cuam tshuam nrog TIE-2 (r = 0.454, p < 0.001) thiab AR (r=0.561, p < 0.001) kev qhia qhia txog kev sib raug zoo [ 28] ib. Txoj haujlwm txaus nyiam los ntawm pab pawg no qhia tau hais tias tsis yog tsuas yog ua testosterone ntxiv txhim kho urethral vascularity tab sis nws kuj muaj tseeb hauv ib puag ncig perioperative.

Lawv kuj qhia tias tom qab kev phais mob angiogenesis yog cov txheej txheem androgen-tsav. Cov nas uas raug phais tsis muaj kab mob urethral nruj thiab nws tseem tsis tau paub meej tias cov kab mob urethral yuav cuam tshuam li cas. Kev ua haujlwm ua ntej tau pom tias cov ntaub so ntswg urethral nruj tau txo qis vascularity [23]; yog li ntawd, nws tsim nyog ntseeg tias tom qab phais mob angiogenesis tseem yuav txhim kho nrog androgen supplementation. Tsis tas li ntawd, pawg sib piv tsis yog TD xwb, tab sis castrate thiab nws muaj peev xwm hais tias cov txiaj ntsig no yuav tsis cuam tshuam rau cov kev kawm uas tsawg dua ntawm TD.

6. Cov lus qhia yav tom ntej

Hauv 5-6 xyoo dhau los, ntau yam tau kawm txog qhov cuam tshuam ntawm testosterone ntawm cov hlab ntsha thiab cov kab mob nruj (Table 1, Ref [18,19,23–28]). Txawm li cas los xij, tseem muaj ntau txoj haujlwm yuav tsum tau ua raws li qhov chaw tawm tshiab no txhais mus rau kev kho mob. Ua ntej, lub luag haujlwm ntawm testosterone hauv urethral stricture etiology tseem tsis meej.

Puas muaj qhov ncaj qha pathogenesis qhov uas tsis tshua muaj ntshav testosterone tsim ib puag ncig ischemic ua rau urethral nruj rau cov txiv neej? Yog tias muaj, qhov twg ntawm idiopathic urethral strictures yog qhov thib ob rau TD? Puas yog TD thiab cov hlab ntsha tsis zoo tiv thaiv qhov txhab kho tom qab kev thuam los ntawm iatrogenic lossis straddle trauma? Yog tias qhov no muaj tseeb, ces yog testosterone supplementation tiv thaiv kab mob urethral stricture? Qhov thib ob, nws yog ib qho tseem ceeb kom nkag siab yog tias TD cuam tshuam cov txiaj ntsig ntawm kev phais. Nws yog qhov tseeb tias urethral stricture recurrence tom qab phais yuav raug txo los ntawm kev txhim kho urethral vascularity thiab tom qab qhov txhab kho.

Tsis tas li ntawd, cov kev mob tshwm sim ntawm kev sib deev tom qab urethroplasty tau txais kev saib xyuas tseem ceeb hauv cov ntaub ntawv thiab xav tias yog qhov tshwm sim ntawm vascular insults thaum phais. Lub luag haujlwm ntawm transecting vs non-transecting anastomotic urethroplasty yog ib lub ntsiab lus sib cav heev hauv kev tsim kho urology. Qhov kev sib cav no tsom mus rau cov txiaj ntsig ntawm kev khaws cov ntshav antegrade rau corpus spongiosum.

Ib qho kev sim randomized tswj tsis ntev los no sib piv kev txiav tawm thiab thawj anastomosis (EPA) thiab buccal mucosa graft urethroplasty pom muaj tus nqi siab dua ntawm cov qog nqaij hlav txhaws hauv EPA pawg [29]. Raws li peb kawm paub ntau ntxiv txog qhov cuam tshuam ntawm testosterone ntawm qhov tshwm sim ntawm urethroplasty, nws yuav nthuav kom pom yog tias testosterone tsis tsuas yog hloov cov txiaj ntsig tab sis kuj mus rau kev tsim kho urethral.

7. Cov lus xaus

Vascularity nyob rau hauv lub urethra thiab corpus spongiosum yog kho los ntawm androgen txoj kev. Tsis tas li ntawd, nws tshwm sim ntau tus txiv neej uas muaj kab mob urethral stricture muaj TD. Ntxiv nrog rau testosterone zoo nkaus li txhim kho urethral vascularity hauv cov qauv tsiaj. Raws li cheeb tsam ntawm txoj kev tshawb no txuas ntxiv tshwm sim, peb yuav cia siab tias yuav kawm ntxiv txog urethral stricture etiologies thiab cuam tshuam ntawm testosterone ntawm qhov tshwm sim ntawm kev phais.

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