Androgens and Morphologic Remodeling at Penile and Cardiovascular Levels: A Common Piece in Complicated Puzzles?

Context

Epidemiologic data demonstrate a protective role by normal androgen levels on cardiovascular health and erectile function. Low androgen levels are associated with erectile dysfunction and increased risk of cardiovascular diseases. Both conditions recognize as anatomic substrate a pathologic structural remodeling. Direct androgen effects on male external genitalia, vascular wall, and myocardium have been reported.

Objective

To review current knowledge about androgen-dependent molecular signaling pathways and cellular events within penile and cardiovascular tissues involved in the homeostatic control of morphologic tissue properties and in the development of structural remodeling in presence of normal and low androgen levels, respectively.

Evidence acquisition

A literature search was performed in November 2008 using the commercially available Medline online engine search to retrieve studies (from 1998 to 2008) on the mechanisms mediating the role of androgens on penile and cardiovascular morphologic homeostasis and remodeling. A combination of the following medical subject headings was used: androgens, hypogonadism, vessel tissue architecture, remodeling, cardiovascular system, and penis.

Evidence synthesis

Androgens exert direct beneficial effects on both cardiovascular and penile tissues. Endothelial cells and smooth-muscle cells are the main cellular targets for direct androgen effects in both tissues and are involved in pathologic remodeling in hypogonadal models. At vascular level, androgens promote endothelial cell survival, reduce endothelial expression of proinflammatory markers, and inhibit proliferation and intimal migration of vascular smooth-muscle cells. At penile level, low androgen levels are associated with apoptosis of endothelial cells and smooth-muscle cells. Moreover, low androgen levels impair proliferation, migration, and homing of endothelial progenitor cells as well as myogenic differentiation of mesenchymal progenitor cells.

Conclusions

Normal androgen levels promote vascular and penile homeostasis by direct mechanisms mainly involving endothelial cells and smooth-muscle cells. Low androgen levels are associated with impairments of such mechanisms, leading to pathologic structural remodeling.     

Comparative Assessment of Antimicrobial Activities of Antibiotic-Treated Penile Prostheses

Background

Although infections associated with penile implants are relatively infrequent, they result in serious medical consequences. Because treatment of these infections usually requires removal of the infected penile implant, prevention of infection is crucial. Since bacterial colonization of the implant is a prelude to clinical infection, antimicrobial modification of the devices may inhibit device colonization and subsequent infection.

Objective

We compared the spectrum and durability, both in vitro and in vivo, of two antibiotic-treated penile prostheses: InhibiZone implants pre-impregnated with minocycline and rifampin (M/R) and Titan implants dipped in vancomycin.

Design, setting, and participants

1 × 1-cm cylinder segments of (1) control untreated, (2) M/R-impregnated, and (3) vancomycin-dipped implants were studied. Baseline zones of inhibition (ZI) were determined against clinical isolates, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant S. epidermidis (MRSE), vancomycin-resistant Enterococcus (VRE), and Escherichia coli. In addition, ZI against methicillin-susceptible S. aureus were compared both in vitro after being washed in a flow chamber and after subcutaneous implantation in rabbits for 1, 2, 7, and 14 d.

Measurements

ZI were measured as the diameter of the clear zone around each test device minus the external diameter of the device.

Results and limitations

Implants pre-impregnated with M/R displayed a broader spectrum of antimicrobial activity than vancomycin-dipped implants against both gram-positive and -negative bacteria. The M/R-impregnated devices also yielded significantly larger zones of inhibition against S. aureus than vancomycin-dipped implants, both in vitro (p < 0.003) and in vivo throughout the 14-d period of device implantation in rabbits (p ≤ 0.03).

Conclusions

Penile prostheses impregnated with M/R have a broader spectrum in vitro and a more durable antimicrobial activity in vitro and in an animal model than implants dipped in vancomycin. Therefore, along with being a more practical model for incorporating antimicrobials onto the device, the use of implants pre-impregnated with M/R may help reduce the incidence of penile implant infection.     

Leg Endoscopic Groin Lymphadenectomy (LEG Procedure): Step-by-Step Approach to a Straightforward Technique

Background

Inguinofemoral lymphadenectomy can serve as a diagnostic and potentially therapeutic procedure in a variety of malignancies, including those of the genitalia and the skin. Historically, this procedure was associated with significant morbidity.

Objective

We hypothesized that both superficial and deep groin dissection (complete inguinofemoral lymphadenectomy) could be performed endoscopically, in a step-by-step manner, with low morbidity, including those patients with obesity and previously treated groins.

Design, setting, and participants

Twenty-five groin dissections were undertaken in 16 patients, male and female, over a 12-mo time period.

Surgical procedure

The femoral triangle was marked. An initial fingers’ breadth–sized incision was made 3 cm below the apex of the femoral triangle. Finger dissection was used to develop the skin flaps at the apex of the triangle out to two additional 10-mm ports. The anterior space was dissected, and, following that, the saphenous vein was transected distally with an endoscopic stapler. The lateral planes on the adductor longus and sartorius muscles were developed, and, finally, the posterior plane was developed, lifting the packet off the fascia lata. Deep femoral nodes were removed as well. The saphenofemoral junction was transected and the packet was removed. A drain was placed.

Measurements

The number of lymph nodes harvested was recorded. The development of skin complications, leg edema, and deep venous thrombosis was recorded as well.

Results and limitations

The average length of procedure was 147 min. The mean number of lymph nodes harvested was nine. A groin seroma requiring further drainage was observed in one patient. Cellulitis was observed in two patients.

Conclusions

Leg endoscopic groin lymphadenectomy (LEG procedure) is straightforward to learn, with operative times that parallel the open procedure. Less morbidity has been observed in our first group of patients compared to contemporary open series.     

Scanning with 18F-FDG-PET/CT for Detection of Pelvic Nodal Involvement in Inguinal Node-Positive Penile Carcinoma

Background

Penile carcinoma patients with inguinal lymph node involvement (LNI) have an increased risk for pelvic nodal involvement with or without distant metastases.

Objective

To evaluate the diagnostic accuracy of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) with computed tomography (CT; 18F-FDG PET/CT) scanning in determining further metastatic spread in patients with tumour-positive inguinal nodes.

Design, setting, and participants

Eighteen patients with penile squamous cell carcinoma with unilateral or bilateral cytologically tumour-positive inguinal disease underwent whole-body 18F-FDG-PET/CT scanning for tumour staging.

Measurements

Images were blindly assessed by two nuclear medicine physicians. All scans were evaluated for pelvic nodal involvement per basin and for distant metastases. Histopathology (when available), radiologic imaging, and clinical follow-up (with a minimum of 1 yr) served as a reference standard. The diagnostic value of PET/CT scanning for predicting pelvic nodal involvement was evaluated using standard statistical methods.

Results and limitations

The reference was available in 28 of the 36 pelvic basins. Of the 11 tumour-positive pelvic basins, 10 were correctly predicted by PET/CT scan, as were all 17 tumour-negative pelvic basins. PET/CT scan showed a sensitivity of 91%, a specificity of 100%, a diagnostic accuracy of 96%, a positive predictive value of 100%, and a negative predictive value of 94% in detecting pelvic nodal involvement. Additionally, PET/CT scans showed distant metastases in five patients. In four patients, the presence of distant metastases could be confirmed, while in one patient, no radiologic confirmation was found for that particular lesion. A potential limitation is that the diagnostic accuracy of PET/CT scanning was calculated on 28 pelvic basins only. Furthermore, no comparison was made with conventional CT scans, as not all patients had undergone contrast-enhanced CT scans.

Conclusions

PET/CT scanning appears promising for detecting pelvic lymph node metastases with great accuracy, and it identifies distant metastases in penile carcinoma patients with inguinal LNI. In our practice, PET/CT scanning has become part of routine staging in such patients.     

预测淋巴结转移阴茎癌术后复发的分类及回归树分析

目的:通过分类及回归树分析来评估淋巴结转移阴茎癌术后的复发风险。方法:回顾性分析1990-2008年60例接受手术治疗的淋巴结转移阴茎癌患者的临床资料和预后。收集淋巴结相关因素,诸如阳性淋巴结数目、单侧或双侧腹股沟淋巴结转移、盆腔淋巴结受累和淋巴结外侵犯情况。采用分类及回归树分析建立淋巴结转移阴茎癌复发风险的回归树模型,并在本组患者中进行验证。结果:建立淋巴结转移阴茎癌复发风险分组的回归树模型。阳性淋巴结数目和淋巴结外侵犯是重要的预后指标。通过该回归树模型将淋巴结转移阴茎癌患者分成4组,生存分析结果显示这4组患者的无复发生存率差异有统计学意义(P<0.05)。结论:通过分类及回归树分析建立回归树模型可准确区分淋巴结转移阴茎癌患者的复发风险,有助于临床制定个体化的治疗决策。     

Stimulation of dopamine receptors in the paraventricular nucleus of the hypothalamus of male rats induces penile erection and increases extra-cellular dopamine in the nucleus accumbens: Involvement of central oxytocin

The effect of a pro-erectile dose of apomorphine, a mixed dopamine receptor agonist, and of PD-168077 (N-[4-(2-cyanophenyl)piperazin-1-ylmethyl]-3-methylbenzamide maleate), a selective dopamine D4 receptor agonist, injected into the paraventricular nucleus of the hypothalamus on the concentration of extra-cellular dopamine and its main metabolite 3,4-dihydroxyphenylacetic acid (DOPAC) in the dialysate from the nucleus accumbens was studied in male rats. As expected, apomorphine (0.1microg) and PD-168077 (0.1microg) induced penile erection episodes, which occurred concomitantly to an increase in extra-cellular dopamine and DOPAC concentration in the dialysate from the shell of the nucleus accumbens, as measured by intracerebral microdialysis. When induced by apomorphine, these effects were reduced by 80% by raclopride, a selective D2/D3 receptor antagonist (1microg) and only by 40-45% by L-745,870 (1microg), a selective dopamine D4 receptor antagonist. When induced by PD-168077, these effects were reduced by more than 80% by L-745,870 (1microg), but only by 35-40% by raclopride. Irrespective of the dopamine agonist used to induce penile erection, the pro-erectile effect and the concomitant increase in dopamine and DOPAC concentration in the nucleus accumbens dialysate were almost completely abolished by d(CH(2))(5)Tyr(Me)(2)-Orn(8)-vasotocin(1microg), a potent oxytocin receptor antagonist, given into the lateral ventricles. The present results suggest that stimulation of dopamine receptors (mainly of the D2 to D4 subtype) in the paraventricular nucleus induces the release of oxytocin in brain areas that influence the activity of mesolimbic dopaminergic neurons mediating the appetitive and reinforcing effects of sexual activity. This provides evidence for a role of oxytocin in neural circuits that integrate the activity of neural pathways controlling the consummatory aspects of sexual behaviour (e.g., penile erection) with those controlling sexual motivation and sexual arousal.     

The natural history of Peyronie's disease: an ultrasonography-based study

OBJECTIVES: To define ultrasonographic patterns reflecting different states of Peyronie's disease (PD) and to use them to evaluate the natural history of the disease. MATERIAL AND METHODS: Diagnosis of PD was based on medical and sexual history, physical examination, intracavernosal injection test, and penile ultrasonography. Patients with penile fracture history were excluded from the study. Three groups were formed according to ultrasonographic patterns: solitary hyperechoic lesion without acoustic shadow (group A), moderately hyperechoic multiple scattered calcified lesions with acoustic shadows (group B), dense calcified hyperechoic plaque with acoustic shadow (group C). All patients entered a watchful waiting protocol for 1 yr followed by a new penile ultrasonography. RESULTS: Ninety-five 95 patients with PD were included in the study (mean age, 57.2+/-9.1 yr; mean duration of disease, 12.9+/-8.9 mo). Risk factors associated with cardiovascular disease were present in 79 of 95 patients (83.16%). Eleven (11.6%), 35 (36.8%), and 49 (51.6%) patients were classified into groups A, B and C, respectively. At the end of the study, in group A, reduction of fibrotic lesions and curvature angle was noticed in 9 of 11 (81.8%) patients, whereas plaque formation was noticed in 2 of 11 (18.2%) patients. In group B, plaque and curvature reduction was noticed in 15 of 35 (42.9%) and 12 of 35 (34.3%) respectively, whereas in the rest a dense calcified plaque was noticed. In group C, no ultrasonographic evidence of improvement was noticed; curvature angle was reduced in 4 of 49 (8.2%), owing to the extension of the plaque circumferentially. Significant hemodynamic changes were noticed at the two time points tested (30.53% diagnosed with vascular disease at baseline vs. 46.32% at the end of the study, p=0.03). CONCLUSIONS: Corporal ultrasonography in patients with PD allows objective evaluation and classification of disease. The density of echogenic areas and presence of acoustic shadows are predictors of disease stability.     

Neurofibromatosis type 1 with external genitalia involvement presentation of 4 patients

Genitourinary neurofibromas with clitoral involvement in neurofibromatosis type 1 are rare, and even more infrequent are the neurofibromas involving genitalia in males. The most frequent presenting sign of neurofibroma in females is clitoromegaly with pseudopenis, and enlarged penis is the most common sign in males. Labium majus neurofibroma not associated with clitoral involvement is extremely rare. Magnetic resonance imaging demonstration of the neurofibromas has seldom been reported. We report 4 children, 3 girls and 1 boy, with plexiform neurofibromas involving the external genitalia. Three of the 4 patients had histologic confirmation of neurofibroma. Two girls with clitoral hypertrophy had a neurofibroma that infiltrated the clitoris and extended unilaterally to the lower bladder wall. One girl had a plexiform neurofibroma that affected a labium. One boy with asymmetric penile hypertrophy since 2 years of age and ipsilateral gluteal hypertrophy had plexiform neurofibromas that extended between the left lumbogluteal and penile regions, infiltrating the left rectum wall and bladder with compression of both structures, the left prostate, and the left half of the cavernous corpi with hypertrophy of this part and asymmetry of the penis. Magnetic resonance imaging demonstrated in all patients that external genitalia and plexiform neurofibroma formed images of nondetachable structures. However, hermaphroditism was discarded by chromosomal study in all 3 girls before ratifying the diagnosis of external genitalia neurofibroma.     

Lymph node metastases and prognosis in penile cancer

Lymph node status is a key prognostic factor in penile squamous cell carcinoma. Recently, growing evidence indicates a multimodality approach consisting of neoadjuvant chemotherapy followed by consolidation surgery improves the outcome of locally advanced penile cancer. Thus, accurate estimation of survival probability in node‐positive penile cancer is critical for treatment decision making, counseling of patients and follow‐up scheduling. This article reviewed evolving developments in assessing the risk for cancer progression based on lymph node related variables, such as the number of metastatic lymph nodes, bilateral lymph node metastases, the ratio of positive lymph nodes, extracapsular extension of metastatic lymph nodes, pelvic lymph node metastases, metastatic deposit in sentinel lymph nodes and N stage in TNM classification. Controversial issues surrounding the prognostic value of these nodal related predictors were also discussed.     

一氧化氮介导离体犬阴茎血管及海绵体平滑肌的胆碱能性舒张

应用离体组织灌流方法，观察了犬阴茎血管及海绵体组织的胆碱能性舒张效应。结果显示，阴茎血管及海绵体组织对乙酰胆碱（Ａｃｈ）均能产生浓度依赖性舒张效应，且被左旋硝基精氨酸（ＬＮＮＡ）、亚甲蓝（ＭＢ）及阿托品抑制，说明这种舒张效应由一氧化氮介导。Ｌ－ＮＮＡ能使海绵体组织及阴部内动脉的静息张力显著上升，提示该组织中基础一氧化氮释放的存在。外源性一氧化氮能使各种组织产生完全性舒张反应，说明一氧化氮是阴茎组织强有力的舒张因子。