In most types of erectile dysfunction, particularly in advanced stages, typical pathological features observed are reduced parenchymal cells coupled with increased tissue fibrosis. However, the current treatment methods have shown limited success in reversing these pathologic changes. Recent research has revealed that changes in autophagy levels, along with alterations in apoptosis and fibrosis-related proteins, are linked to the progression of erectile dysfunction, suggesting a significant association. Autophagy, known to significantly affect cell fate and tissue fibrosis, is currently being explored as a potential treatment modality for erectile dysfunction. However, these present studies are still in their nascent stage, and there are limited experimental data available. This review analyzes erectile dysfunction from a pathological perspective. It provides an in-depth overview of how autophagy is involved in the apoptotic processes of smooth muscle and endothelial cells and its role in the fibrotic processes occurring in the cavernosum. This study aimed to develop a theoretical framework for the potential effectiveness of autophagy in preventing and treating erectile dysfunction, thus encouraging further investigation among researchers in this area.
Male ; Humans ; Autophagy/physiology* ; Apoptosis/physiology* ; Erectile Dysfunction/physiopathology* ; Fibrosis ; Penis/pathology* ; Animals ; Endothelial Cells/pathology* ; Myocytes, Smooth Muscle/pathology*

Stem cell treatment may enhance erectile dysfunction (ED) in individuals with cavernous nerve injury (CNI). Nevertheless, no investigations have directly ascertained the implications of varying amounts of human umbilical cord-derived mesenchymal stem cells (HUC-MSCs) on ED. We compare the efficacy of three various doses of HUC-MSCs as a therapeutic strategy for ED. Sprague-Dawley rats (total = 175) were randomly allocated into five groups. A total of 35 rats underwent sham surgery and 140 rats endured bilateral CNI and were treated with vehicles or doses of HUC-MSCs (1 × 10 6 cells, 5 × 10 6 cells, and 1 × 10 7 cells in 0.1 ml, respectively). Penile tissues were harvested for histological analysis on 1 day, 3 days, 7 days, 14 days, 28 days, 60 days, and 90 days postsurgery. It was found that varying dosages of HUC-MSCs enhanced the erectile function of rats with bilateral CNI and ED. Moreover, there was no significant disparity in the effectiveness of various dosages of HUC-MSCs. However, the expression of endothelial markers (rat endothelial cell antigen-1 [RECA-1] and endothelial nitric oxide synthase [eNOS]), smooth muscle markers (alpha smooth muscle actin [α-SMA] and desmin), and neural markers (neurofilament [RECA-1] and neurogenic nitric oxide synthase [nNOS]) increased significantly with prolonged treatment time. Masson's staining demonstrated an increased in the smooth muscle cell (SMC)/collagen ratio. Significant changes were detected in the microstructures of various types of cells. In vivo imaging system (IVIS) analysis showed that at the 1 st day, the HUC-MSCs implanted moved to the site of damage. Additionally, the oxidative stress levels were dramatically reduced in the penises of rats administered with HUC-MSCs.
Male ; Animals ; Erectile Dysfunction/metabolism* ; Rats, Sprague-Dawley ; Mesenchymal Stem Cell Transplantation/methods* ; Rats ; Penis/pathology* ; Humans ; Disease Models, Animal ; Umbilical Cord/cytology* ; Peripheral Nerve Injuries/complications* ; Mesenchymal Stem Cells ; Nitric Oxide Synthase Type III/metabolism* ; Actins/metabolism* ; Nitric Oxide Synthase Type I/metabolism*

Low-intensity pulsed ultrasound (LIPUS) is a non-invasive sonodynamic therapy that has been approved by the U.S. Food and Drug Administration for clinical use. Clinical trials have demonstrated that LIPUS ameliorates mild-to-moderate erectile dysfunction without adverse events. Histological analysis of the corpus cavernosum suggests that the therapeutic benefits of LIPUS may be attributed to alleviation of fibrosis, enhanced neovascularization, and promotion of innervation. Further investigations have revealed that LIPUS facilitates cavernous tissue repair through non-thermal mechanisms, including a cavitation effect, acoustic streaming, mass transfer enhancement, and direct mechanical stimulation. Mechanobiological transduction triggers molecular signaling cascades within endogenous cavernous cells, thereby stimulating cell proliferation, angiogenesis, extracellular matrix remodeling, and stem cell differentiation. Although LIPUS has the potential to induce cavernous rehabilitation in the treatment of erectile dysfunction, further investigations are necessary to elucidate the mechanisms via which LIPUS regulates each type of cavernous cell to determine the optimal parameters for this innovative therapy.
Male ; Humans ; Erectile Dysfunction/therapy* ; Ultrasonic Therapy/methods* ; Penis/pathology* ; Ultrasonic Waves

OBJECTIVE: To observe the therapeutic effect of governor vessel moxibustion combined with wenyang yiqi qiwei decoction on erectile dysfunction (ED) with spleen-kidney deficiency and to explore the possible mechanism. METHODS: A total of 130 ED patients with spleen-kidney deficiency were randomized into an observation group (65 cases, 2 cases dropped off) and a control group (65 cases, 3 cases dropped off). The control group was given wenyang yiqi qiwei decoction orally, one dose daily. On the basis of the treatment in the control group, governor vessel moxibustion was applied from Dazhui (GV 14) to Yaoshu (GV 2) in the observation group, 110 min a time, once a day. The treatment of 4 weeks was required in both groups. Before and after treatment, 5-question international index of erectile function (IIEF-5) score, erection quality scale (EQS) score, erectile hardness assessment (EHS) score, TCM syndrome score, serum testosterone (T) level and vascular endothelial function indexes (prostaglandin I2 [PGI2], endothelin-1 [ET-1] and nitric oxide [NO] levels) were observed respectively, and the clinical efficacy was evaluated in both groups. RESULTS: After treatment, the scores of IIEF-5, EQS, EHS and serum levels of T, PGI2, NO were increased compared before treatment (P<0.01), the TCM syndrome scores and serum ET-1 levels were decreased compared before treatment (P<0.01) in the two groups; the scores of IIEF-5, EQS, EHS and serum levels of T, PGI2, NO in the observation group were higher than those in the control group (P<0.01, P<0.05), the TCM syndrome score and serum ET-1 level were lower than those in the control group (P<0.01, P<0.05). The total effective rate was 88.9% (56/63) in the observation group, which was superior to 74.2% (46/62) in the control group (P<0.05). CONCLUSION Governor vessel moxibustion combined with wenyang yiqi qiwei decoction can improve the erectile function and increase the erection hardness and quality in ED patients with spleen-kidney deficiency, its mechanism may relate to improving serum T level and vascular endothelial function.
Humans ; Male ; Administration, Oral ; Drugs, Chinese Herbal/therapeutic use* ; Erectile Dysfunction/therapy* ; Kidney/pathology* ; Kidney Diseases/complications* ; Moxibustion ; Spleen/pathology* ; Splenic Diseases/complications* ; Testosterone/blood* ; Combined Modality Therapy

Male patients with prolactinomas usually present with typical hyperprolactinemia symptoms, including sexual dysfunction and infertility. However, clinical factors related to sexual dysfunction and surgical outcomes in these patients remain unclear. This study aimed to investigate the outcomes of male patients with prolactinomas after transsphenoidal surgery and the risk factors affecting sexual dysfunction. This study was conducted on 58 male patients who underwent transsphenoidal surgery for prolactinomas between May 2014 and December 2020 at the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. We evaluated the sexual function of patients before and after surgery through International Index of Erectile Function-5 scores, libido, and frequency of morning erection. Of the 58 patients, 48 (82.8%) patients had sexual intercourse preoperatively. Among those 48 patients, 41 (85.4%) patients presented with erectile dysfunction. The preoperative International Index of Erectile Function-5 scores in patients with macroprolactinomas were significantly higher than those in patients with giant prolactinomas (17.63 ± 0.91 vs 13.28 ± 1.43; P = 0.01). Postoperatively, the incidence of erectile dysfunction was 47.9%, which was significantly lower than that preoperatively (85.4%; P = 0.01). Twenty-eight (68.3%) patients demonstrated an improvement in erectile dysfunction. Tumor size and invasiveness were significantly correlated with the improvement of erectile dysfunction. Preoperative testosterone <2.3 ng ml^-1 was an independent predictor of improvement in erectile dysfunction. In conclusion, our results indicated that tumor size and invasiveness were important factors affecting the improvement of sexual dysfunction in male patients with prolactinoma. The preoperative testosterone level was an independent predictor related to the improvement of erectile dysfunction.
Humans ; Male ; Prolactinoma/surgery* ; Erectile Dysfunction/etiology* ; Retrospective Studies ; Sexual Dysfunction, Physiological/complications* ; Testosterone ; Pituitary Neoplasms/pathology*

Silent information regulator 2-related enzyme 1 (SIRT1) is an aging-related protein activated with aging. Herein, we evaluated the role of SIRT1 in aging-related erectile dysfunction. The expression of SIRT1 was modulated in aged Sprague-Dawley rats following intragastric administration of resveratrol (Res; 5 mg kg^-1), niacinamide (NAM; 500 mg kg^-1) or Res (5 mg kg^-1) + tadalafil (Tad; phosphodiesterase-5 [PDE5] inhibitor; 5 mg kg^-1) for 8 weeks. Then, we determined erectile function by the ratio of intracavernosal pressure (ICP)/mean systemic arterial pressure (MAP). Cavernosal tissues were extracted to evaluate histological changes, cell apoptosis, nitric oxide (NO)/cyclic guanosine monophosphate (cGMP), the superoxide dismutase (SOD)/3,4-methylenedioxyamphetamine (MDA) level, and the expression of SIRT1, p53, and forkhead box O3 (FOXO3a) using immunohistochemistry, terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine 5'-triphosphate (dUTP) nick-end labeling (TUNEL), enzyme-linked immunosorbent assays, and western blot analysis. Compared with the control, Res treatment significantly improved erectile function, reflected by an increased content of smooth muscle and endothelium, NO/cGMP and SOD activity, and reduced cell apoptosis and MDA levels. The effect of Res was improved by adding Tad. In addition, the protein expression of SIRT1 was increased in the Res group, accompanied by decreased p53 and FOXO3a levels. In addition, inhibition of SIRT1 by NAM treatment resulted in adverse results compared with Res treatment. SIRT1 activation ameliorated aging-related erectile dysfunction, supporting the potential of SIRT1 as a target for erectile dysfunction treatment.
Animals ; Male ; Rats ; Cyclic GMP/metabolism* ; Erectile Dysfunction/metabolism* ; Nitric Oxide/metabolism* ; Penile Erection ; Penis/pathology* ; Phosphodiesterase 5 Inhibitors/pharmacology* ; Rats, Sprague-Dawley ; Sirtuin 1/metabolism* ; Superoxide Dismutase/metabolism* ; Tumor Suppressor Protein p53/metabolism*

We wanted to determine whether shear wave elastography (SWE) could be used to evaluate the aging degree of the corpus cavernosum (CC) and to identify the histological basis of changes in SWE measurements during the aging process. We performed a cross-sectional study enrolling healthy participants of different ages. We measured the Young's modulus (YM) of the penile CCs by SWE and assessed erectile function using the International Index of Erectile Function-5 (IIEF-5). Histological investigation was performed in surgically resected penile specimens from a separate group of patients to examine the smooth muscle and collagen content of the CCs. Furthermore, we measured the YM, erectile function, smooth muscle, and collagen content of the CCs in different age groups of rats. Finally, we enrolled 210 male volunteers in this study. The YM of the CC (CCYM) was positively correlated with age (r = 0.949, P < 0.01) and negatively correlated with erectile function (r = -0.843, P < 0.01). Histological examinations showed that CCs had increased collagen content but decreased smooth muscle content with increased age. The same positive correlation between CCYM and age was also observed in the animal study. In addition, the animal study showed that older rats, with increased CCYM and decreased erectile function, had lower smooth muscle content and higher collagen content. SWE can noninvasively and quantitatively evaluate the aging degree of the CC. Increased collagen content and decreased smooth muscle content might be the histological basis for the effect of aging on the CC and the increase in its YM.
Humans ; Male ; Rats ; Animals ; Erectile Dysfunction ; Elasticity Imaging Techniques ; Cross-Sectional Studies ; Penis/pathology* ; Penile Erection/physiology* ; Aging ; Collagen

Sexual disorders following retroperitoneal pelvic lymph node dissection (RPLND) for testis tumor can affect the quality of life of patients. The aim of the current study was to investigate several different andrological outcomes, which may be influenced by robot-assisted (RA) RPLND. From January 2012 to March 2020, 32 patients underwent RA-RPLND for stage I nonseminomatous testis cancer or postchemotherapy (PC) residual mass. Modified unilateral RPLND nerve-sparing template was always used. Major variables of interest were erectile dysfunction (ED), premature ejaculation (PE), dry ejaculation (DE), or orgasm alteration. Finally, fertility as well as the fecundation process (sexual intercourse or medically assisted procreation [MAP]) was investigated. Ten patients (31.3%) presented an andrological disorder of any type after RA-RPLND. Hypospermia was present in 4 (12.5%) patients, DE (International Index of Erectile Function-5 [IIEF-5] <25) in 3 (9.4%) patients, and ED in 3 (9.4%) patients. No PE or orgasmic alterations were described. Similar median age at surgery, body mass index (BMI), number of nodes removed, scholar status, and preoperative risk factor rates were identified between groups. Of all these 10 patients, 6 (60.0%) were treated at the beginning of our robotic experience (2012-2016). Of all 32 patients, 5 (15.6%) attempted to have a child after RA-RPLND. All of these 5 patients have successfully fathered children, but 2 (40.0%) required a MAP. In conclusion, a nonnegligible number of andrological complications occurred after RA-RPLND, mainly represented by ejaculation disorders, but ED occurrence and overall sexual satisfaction deficit should be definitely considered. No negative impact on fertility was described after RA-RPLND.
Male ; Child ; Humans ; Robotics ; Quality of Life ; Retrospective Studies ; Neoplasms, Germ Cell and Embryonal/surgery* ; Testicular Neoplasms/pathology* ; Lymph Node Excision/adverse effects* ; Retroperitoneal Space/surgery* ; Erectile Dysfunction/surgery* ; Treatment Outcome

The aim of this study was to investigate the mechanism by which a diet inducing high hyperhomocysteinemia (HHcy) leads to the deterioration of erectile function in rats and whether this is inhibited by expression of the human tissue kallikrein-1 (hKLK1) gene. We established a rat model of HHcy by feeding methionine (Met)-rich diets to male Sprague-Dawley (SD) rats. Male wild-type SD rats (WTRs) and transgenic rats harboring the hKLK1 gene (TGRs) were fed a normal diet until 10 weeks of age. Then, 30 WTRs were randomly divided into three groups as follows: the control (n = 10) group, the low-dose (4% Met, n = 10) group, and the high-dose (7% Met, n = 10) group. Another 10 age-matched TGRs were fed the high-dose diet and designated as the TGR+7% Met group. After 30 days, in all four groups, erectile function was measured and penile tissues were harvested to determine oxidative stress, endothelial cell content, and penis fibrosis. Compared with the 7% Met group, the TGR+7% Met group showed diminished HHcy-induced erectile dysfunction (ED), indicating the improvement caused by hKLK1. Regarding corpus cavernosum endothelial cells, hKLK1 preserved endothelial cell-cell junctions and endothelial cell content, and activated protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) signaling. Fibrosis assessment indicated that hKLK1 preserved normal penis structure by inhibiting apoptosis in the corpus cavernosum smooth muscle cells. Taken together, these findings showed that oxidative stress, impaired corpus cavernosum endothelial cells, and severe penis fibrosis were involved in the induction of ED by HHcy in rats, whereas hKLK1 preserved erectile function by inhibiting these pathophysiological changes.
Animals ; Apoptosis ; Diet ; Endothelial Cells ; Erectile Dysfunction/prevention & control* ; Fibrosis ; Humans ; Hyperhomocysteinemia/complications* ; Male ; Methionine ; Oxidative Stress ; Penis/pathology* ; Rats ; Rats, Sprague-Dawley ; Rats, Transgenic ; Signal Transduction/genetics* ; Tissue Kallikreins/genetics*

We aimed to determine whether combination of LIM-kinase 2 inhibitor (LIMK2i) and phosphodiesterase type-5 inhibitor (PDE5i) could restore erectile function through suppressing cavernous fibrosis and improving cavernous apoptosis in a rat model of cavernous nerve crush injury (CNCI). Seventy 12-week-old Sprague-Dawley rats were equally distributed into five groups as follows: (1) sham surgery (Group S), (2) CNCI (Group I), (3) CNCI treated with daily intraperitoneal administration of 10.0 mg kg^-1 LIMK2i (Group I + L), (4) daily oral administration of 20.0 mg kg^-1 udenafil, PDE5i (Group I + U), and (5) combined administration of 10.0 mg kg^-1 LIMK2i and 20.0 mg kg^-1 udenafil (Group I + L + U). Rats in Groups I + L, I + U, and I + L + U were treated with respective regimens for 2 weeks after CNCI. At 2 weeks after surgery, erectile response was assessed using electrostimulation. Penile tissues were processed for histological studies and western blot. Group I showed lower intracavernous pressure (ICP)/mean arterial pressure (MAP), lower area under the curve (AUC)/MAP, decreased immunohistochemical staining for alpha-smooth muscle (SM) actin, higher apoptotic index, lower SM/collagen ratio, increased phospho-LIMK2-positive fibroblasts, decreased protein kinase B/endothelial nitric oxide synthase (Akt/eNOS) phosphorylation, increased LIMK2/cofilin phosphorylation, and increased protein expression of fibronectin, compared to Group S. In all three treatment groups, erectile responses, protein expression of fibronectin, and SM/collagen ratio were improved. Group I + L + U showed greater improvement in erectile response than Group I + L. SM content and apoptotic index in Groups I + U and I + L + U were improved compared to those in Group I. However, Group I + L did not show a significant improvement in SM content or apoptotic index. The number of phospho-LIMK2-positive fibroblasts was normalized in Groups I + L and I + L + U, but not in Group I + U. Akt/eNOS phosphorylation was improved in Groups I + U and I + L + U, but not in Group I + L. LIMK2/cofilin phosphorylation was improved in Groups I + L and I + L + U, but not in Group I + U. Our data indicate that combined treatment of LIMK2i and PDE5i immediate after CN injury could improve erectile function by improving cavernous apoptosis or eNOS phosphorylation and suppressing cavernous fibrosis. Rectification of Akt/eNOS and LIMK2/cofilin pathways appears to be involved in their improvement.
Animals ; Apoptosis/drug effects* ; Arterial Pressure ; Electric Stimulation ; Erectile Dysfunction/pathology* ; Lim Kinases/antagonists & inhibitors* ; Male ; Nerve Crush ; Nitric Oxide Synthase Type III/metabolism* ; Penis/pathology* ; Peripheral Nerve Injuries/pathology* ; Phosphodiesterase 5 Inhibitors/therapeutic use* ; Phosphorylation ; Pyrimidines/therapeutic use* ; Rats ; Rats, Sprague-Dawley ; Sulfonamides/therapeutic use*