Flum Andrew S, Firmiss Paula R, Bowen Diana K, Kukulka Natalie, Delos Santos Grace B, Dettman Robert W, Gong Edward M
Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States.
Developmental Biology, Stanley Manne Children's Research Institute, Chicago, IL, United States.
Front Pediatr. 2017 Jun 7;5:132. doi: 10.3389/fped.2017.00132. eCollection 2017.
Lower urinary tract symptoms secondary to posterior urethral valves (PUV) arise in boys during adolescence. The reasons for this have previously been attributed to increased urine output as boys experience increased growth. Additionally, there are few choices for clinicians to effectively treat these complications. We formed the new hypothesis that increased androgen levels at this time of childhood development could play a role at the cellular level in obstructed bladders. To test this hypothesis, we investigated the role of testosterone on bladder detrusor muscle following injury from partial bladder outlet obstruction (PO) in mice. A PO model was surgically created in juvenile male mice. A group of mice were castrated by bilateral orchiectomy at time of obstruction (CPO). Testosterone cypionate was administered to a group of castrated, obstructed mice (CPOT). Bladder function was assessed by voiding stain on paper (VSOP). Bladders were analyzed at 7 and 28 days by weight and histology. Detrusor collagen to smooth muscle ratio (Col/SM) was calculated using Masson's trichrome stain. All obstructed groups had lower max voided volumes (MVV) than sham mice at 1 day. Hormonally intact mice (PO) continued to have lower MVV at 7 and 28 days while CPO mice improved to sham levels at both time points. In accordance, PO mice had higher bladder-to-body weight ratios than CPO and sham mice demonstrating greater bladder hypertrophy. Histologically, Col/SM was lower in sham and CPO mice. When testosterone was restored in CPOT mice, MVV remained low at 7 and 28 days compared to CPO and bladder-to-body weight ratios were also greater than CPO. Histologic changes were also seen in CPOT mice with higher Col/SM than sham and CPO mice. In conclusion, our findings support a role for testosterone in the fibrotic changes that occur after obstruction in male mice. This suggests that while other changes may occur in adolescent boys that cause complication in boys with PUV, the bladder itself responds to testosterone at the cellular level. This opens the door to a new understanding of pathways that influence bladder fibrosis and could lead to novel approaches to treat boys with PUV.
继发于后尿道瓣膜（PUV）的下尿路症状在青春期男孩中出现。以前认为其原因是随着男孩生长加速尿量增加。此外，临床医生有效治疗这些并发症的选择很少。我们提出了一个新的假设，即在儿童发育的这个阶段雄激素水平升高可能在细胞水平上对梗阻性膀胱起作用。为了验证这一假设，我们研究了睾酮对小鼠部分膀胱出口梗阻（PO）损伤后膀胱逼尿肌的作用。在幼年雄性小鼠中通过手术建立PO模型。一组小鼠在梗阻时通过双侧睾丸切除术去势（CPO）。将环戊丙酸睾酮给予一组去势且梗阻的小鼠（CPOT）。通过纸上排尿染色（VSOP）评估膀胱功能。在第7天和第28天通过重量和组织学分析膀胱。使用Masson三色染色计算逼尿肌胶原与平滑肌比率（Col/SM）。所有梗阻组在第1天时的最大排尿量（MVV）均低于假手术小鼠。激素完整的小鼠（PO）在第7天和第28天时MVV仍然较低，而CPO小鼠在两个时间点均改善至假手术水平。相应地，PO小鼠的膀胱与体重比高于CPO和假手术小鼠，表明膀胱肥大更明显。组织学上，假手术和CPO小鼠的Col/SM较低。当在CPOT小鼠中恢复睾酮时，与CPO相比，在第7天和第28天时MVV仍然较低，并且膀胱与体重比也大于CPO。在CPOT小鼠中也观察到组织学变化，其Col/SM高于假手术和CPO小鼠。总之，我们的研究结果支持睾酮在雄性小鼠梗阻后发生的纤维化变化中起作用。这表明虽然青春期男孩可能会发生其他导致PUV男孩出现并发症的变化，但膀胱本身在细胞水平上对睾酮有反应。这为影响膀胱纤维化的途径带来了新的理解，并可能导致治疗PUV男孩的新方法。
