Corpus Cavernosum Research Articles

Accumulation of Adipocytes in Penile Corpus Cavernosum May Contribute to Venous Leakage and Veno-Occlusive Dysfunction in Patients with Testosterone Deficiency and Erectile Dysfunction

In 2005, we reported that, in the animal model, androgen deprivation resulted in significant changes in the structural elements of the penile corpus cavernosum (CC), including: (1) atrophy of the trabecular smooth muscle, (2) increased deposition of connective tissue, and (3) accumulation of adipocytes in the sub-tunical region. These structural alterations, together with reported decreases in the expression and activity of endothelial nitric oxide synthase (eNOS) and neural nitric oxide synthase (nNOS), are believed to contribute to reduced blood inflow and increased blood outflow, contributing to veno-occlusive dysfunction and erectile dysfunction (ED). More recently, several clinical studies have documented accumulation of adipocytes in the sub-tunical region of the corpora cavernosa from patients with ED, supporting findings reported in the animal models. Here, we summarize the observations from basic and clinical research and advance the hypothesis that testosterone deficiency contributes to significant changes in the structural integrity of the CC, resulting in atrophy of the trabecular smooth muscle and contributing to reduced vascular smooth muscle relaxation and diminished blood inflow into the penis, resulting in a failure to fill. In addition, atrophy of the trabecular smooth muscle, accumulation of adipocytes in the sub-tunical region, and increased deposition of connective tissue contribute to veno-occlusive dysfunction and a failure to maintain erection. It is postulated that testosterone treatment in men with testosterone deficiency may reverse the structural alterations in the CC and improve erectile function.

STIM/Orai Inhibition as a Strategy for Alleviating Diabetic Erectile Dysfunction Through Modulation of Rat and Human Penile Tissue Contractility and in vivo Potentiation of Erectile Responses

Stromal interaction molecule (STIM)/Orai calcium entry system appears to have a role in erectile dysfunction (ED) pathophysiology but its specific contribution to diabetic ED was not elucidated. To evaluate STIM/Orai inhibition on functional alterations associated with diabetic ED in rat and human penile tissues and on in vivo erectile responses in diabetic rats. Rat corpus cavernosum (RCC) strips from nondiabetic (No DM) and streptozotocin-induced diabetic (DM) rats and human penile resistance arteries (HPRA) and corpus cavernosum (HCC) from ED patients undergoing penile prosthesis insertion were functionally evaluated in organ chambers and wire myographs. Erectile function in vivo in rats was assessed by intracavernosal pressure (ICP) responses to cavernous nerve electrical stimulation (CNES). Expression of STIM/Orai elements in HCC was determined by immunofluorescence and immunoblot. Functional responses in RCC, HCC and HPRA and STIM/Orai protein expression in HCC. In vivo erectile responses to CNES. Inhibition of Orai channels with YM-58483 (20 µM) significantly reduced adrenergic contractions in RCC but more effectively in DM. Thromboxane-induced and neurogenic contractions were reduced by STIM/Orai inhibition while defective endothelial, neurogenic and PDE5 inhibitor-induced relaxations were enhanced by YM-58483 (10 µM) in RCC from DM rats. In vivo, YM-58483 caused erections and attenuated diabetes-related impairment of erectile responses. YM-58483 potentiated the effects of PDE5 inhibition. In human tissues, STIM/Orai inhibition depressed adrenergic and thromboxane-induced contractions in ED patients more effectively in those with type 2 diabetes. Diabetes was associated with increased expression of Orai1 and Orai3 in ED patients. Targeting STIM/Orai to alleviate diabetes-related functional alterations of penile vascular tissue could improve erectile function and potentiate therapeutic effects of PDE5 inhibitors in diabetic ED. Improving effects of STIM/Orai inhibition on diabetes-related functional impairment was evidenced in vitro and in vivo in an animal model and validated in human tissues from ED patients. Functional findings were complemented with expression results. Main limitation was low numbers of human experiments due to limited human tissue availability. STIM/Orai inhibition alleviated alterations of functional responses in vitro and improved erectile responses in vivo in diabetic rats, potentiating the effects of PDE5 inhibition. STIM/Orai inhibition was validated as a target to modulate functional alterations of human penile vascular tissue in diabetic ED where Orai1 and Orai3 channels were upregulated. STIM/Orai inhibition could be a potential therapeutic strategy to overcome poor response to conventional ED therapy in diabetic patients. Sevilleja-Ortiz A, El Assar M, García-Gómez B, et al. STIM/Orai Inhibition as a Strategy for Alleviating Diabetic Erectile Dysfunction Through Modulation of Rat and Human Penile Tissue Contractility and in vivo Potentiation of Erectile Responses. J Sex Med 2022;19:1733-1749.

THE BENEFICIAL EFFECT OF INTRACAVERNOSAL INJECTION OF SILDENAFIL ON ERECTILE DYSFUNCTION IN DUTASTERIDE TREATED RATS

Objective: Benign prostatic hyperplasia (BPH) and erectile dysfunction (ED) are the most common illnesses in aged male patients. 5α-reductase inhibitors (5-ARIs) are suggested for the treatment of BPH. Furthermore, the association of 5ARIs with ED has been indicated. This study aimed to investigate the effect of intracavernosal injection of sildenafil on ED in 5ARI treated rats.Material and Method: Sprague-Dawley rats (n=30) were divided into three groups: Control; 10-week dutasteride treatment (0.5 mg/rat/day); and 6-week durasteride treatment followed by a 4-week washout period. In vivo erectile responses were assessed before and after intracavernosal injection of sildenafil (0.3mg/kg/rat). The relaxant and contractile responses of isolated corpus cavernosum were evaluated in in vitro organ bath.Result and Discussion: Prostate weight decreased after 10-week dutasteride treatment. In vivo erectile responses, endothelial and nitrergic relaxation responses were decreased in dutasteride groups. The washout period moderately normalized erectile responses. The intracavernosal injection of sildenafil increased erectile function in treatment groups. Contractile responses were augmented in 10-week dutasteride treated rats. The cessation of the treatment did not alter erectile function as well as endothelial relaxation and nitrergic relaxation. Also, intracavernosal sildenafil caused an improvement in 5ARI treatment-induced ED.

Saxagliptin alleviates erectile dysfunction through increasing stromal cell-derived factor-1 in diabetes mellitus.

Diabetes mellitus-induced erectile dysfunction (DMED) is one of the complications of diabetes and has a poor response to phosphodiesterase type 5 inhibitor, the first-line treatment for ED. Saxagliptin (Sax), a dipeptidyl peptidase-4 inhibitor (DPP-4i), has been officially used in the treatment of type 2 diabetes. Stromal cell-derived factor-1 (SDF-1) is one of the important substrates of DPP-4, and has been proven to be beneficial for several DM complications. However, it is unknown whether Sax contributes to the management of DMED. To explore the effect and possible underlying mechanisms of Sax in the treatment of DMED. The model of DM was established by intraperitoneal injection of streptozotocin. All rats were divided into three groups (n=8 per group): control group, DMED group and DMED+Sax group. In cellular experiments, the corpus cavernosum smooth muscle cells (CCSMCs) were exposed to high glucose (HG), and treated with Sax and AMD3100 (SDF-1 receptor inhibitor). The penile tissue and CCSMCs were harvested for detection. We found that erectile function was impaired in DMED rats compared with the control group, which was partially relieved by Sax. Decreased expression of DPP-4 and increased level of SDF-1 were also observed in DMED+Sax group, together with elevation of PI3K/AKT pathway and inhibition of endothelial dysfunction, oxidative stress and apoptosis in corpus cavernosum. Moreover, Sax could also regulate oxidative stress and apoptosis in CCSMCs under HG condition, which was blocked in part by AMD3100. Sax could alleviate DMED through increasing SDF-1 and PI3K/AKT pathway, in company with moderation of endothelial dysfunction, oxidative stress and apoptosis. Our findings indicated that DPP-4 is may be beneficial to the management of DMED.

Male genital organs of the black-crowned dwarf marmoset (Callibella humilis).

This study provides the first morphological description of the male genital organs of black-crowned dwarf marmoset (Callibella humilis). Internal and external genital organs were similar to other species of non-human primates. However, some shape and size differences were noted. The penile shaft was laterally flattened and comprised of two corpus cavernosus. These were split by a septum up to the level of the glans and then merged to form a single structure. The glans penis had small, keratinized spicules arising from epidermal or dermal projections. The small, fully ossified and well-mineralized penile bone, located at the distal end of the penis, consisted of a bone matrix surrounded by sparse osteoblasts and well-developed internal osteocytes. The penile urethra was lined with columnar pseudostratified epithelium, with areas of simple cuboidal epithelium. The testes were small relative to the body compared to other primate species. The findings of this work may support comparative studies of primate reproductive ecology.

Penile lenghthening original technique using a pubo-cavernous spacer. Long term results from a series of over 200 patients.

We report our long experience in the surgical treatment of patients requesting penile lengthening by suspensory ligament release and placement of a custom-made soft silicone pubo-cavernous spacer. The aim was to show that with this surgical technique the results obtained are maintained over time. It is crucial to achieve postoperative satisfaction of these patients who show fragility and self-esteem problems. From 1999 to 2020, we treated 245 patients with congenital or acquired penile brevity. We carefully analysed the preoperative and postoperative (at 6, 12, 24 and 48 months) penile size of the patients to evaluate whether this technique could allow the long-term maintenance of aesthetic results. We also assessed preoperative erectile function and we focused on the psychological aspects to avoid surgery in patients with dysmorphophobia. This original technique involves the section of the suspensory ligament and the implantation of a silicone spacer between the pubic symphysis and the corpora cavernosa. This spacer is conformed to the patient anatomy and maintains the relationship between the anatomical structures unchanged over time. Sexual self-esteem and patient satisfaction were assessed with the APPSSI questionnaire. The mean increase in penile length was about 2.5 cm in flaccid state and 1.9 cm in stretched state. There were no injuries of the neurovascular bundle or urethra, and no erectile dysfunction was noted. These results persisted at 6, 12, 24 and 48 months without significant differences. Over 80% of patients stated that they were completely satisfied with the results obtained. This satisfaction remained stable along follow up. The section of the suspensory ligament and the implant of the soft silicone spacer provide real penis elongation with satisfactory results that persist over time. This technique avoids the frequent complication of short-term shortening due to the scar adhesions of the edges of the dissected ligament. The high aesthetic satisfaction of patients is stable at controls at 6, 12, 24 and 48 months.

Relaxation mechanisms of chloroform root extracts of Prangos heyniae and Prangos uechtritzii on mouse corpus cavernosum.

Erectile dysfunction (ED) is the inability to achieve/maintain an erection. Because of the side effects, interactions, or ineffectiveness of currently used drugs, novel drug discovery studies are ongoing. The roots of Turkish endemic plants Prangos uechtritzii and Prangos heyniae are traditionally used as aphrodisiacs in Anatolia and contain coumarin-like relaxant compounds. This study aims to reveal the relaxant effect mechanisms of chloroform root extracts of P. heyniae (Ph-CE) and P. uechtritzii (Pu-CE). Isolated organ bath experiments were performed on Swiss albino mouse corpus cavernosum by DMT strip myograph. Relaxant responses to extract (10-7 -10-4 g/ml) were obtained in the presence/absence of NO and H2 S synthesis inhibitors nitro-l-arginine methyl ester (l-NAME, 100 μM) and aminooxyacetic acid (AOAA, 10 mM) respectively. Sodium nitroprusside (SNP, 10-9 to 10-4 M) and Na2 S (10-6 to 3× 10-3 M)-induced relaxations and CaCl2 (10-6 to 10-4 M), KCl (10-2.1 to 10-0.9 M) and phenylephrine (3× 10-8 to 3× 10-5 M)-induced contractions were taken in the presence/absence of the extracts (10-4 g/ml). Relaxations induced by Ph-CE but not by Pu-CE were inhibited in the presence of l-NAME and AOAA. Ph-CE increased Na2 S- and SNP-induced relaxations. Ph-CE and Pu-CE decreased the contractions of KCl, phenylephrine, and CaCl2 . It was concluded that NO and H2 S synthesis/downstream mechanisms play roles in relaxations of Ph-CE but not in Pu-CE-induced relaxations. Inhibition of calcium influx appears to be involved in the relaxant effect of Ph-CE and Pu-CE. Since the extracts act directly by relaxing smooth muscle or through H2 S as well as NO, they may be a potential therapeutic agent in diseases such as ED where the bioavailability of NO is impaired.

GPX4 Alleviates Diabetes Mellitus-Induced Erectile Dysfunction by Inhibiting Ferroptosis.

Pharmacological therapy of diabetes mellitus-induced erectile dysfunction (DMED) is intractable owig to the poor response to phosphodiesterase type 5 inhibitors (PDE5i). The surge in the number of diabetic patients makes it extremely urgent to find a novel therapy for DMED. Ferroptosis is a recently discovered form of cell death evoked by lipid peroxidation and is related to several diabetic complications. GPX4, an important phospholipid hydroperoxidase, can alleviate ferroptosis and maintain redox balance via reducing lipid peroxides. However, whether GPX4 can be a prospective target of DMED needs to be determined. Fifty rats were randomly divided into control group, DMED group, DMED + negative control group (DMED + NC group), DMED + low-dose group (1 × 106 infectious units), and DMED + high-dose group (2 × 106 infectious units). Erectile function was assessed 4 weeks after intracavernous injection of GPX4 or negative control lentivirus. The penile shafts were collected for subsequent molecular biological and histological analysis. The results demonstrated that erectile function of the rats in DMED and DMED + NC groups was extremely impaired and was improved in a dose-dependent manner with GPX4 lentivirus (GPX4-LV) injection. Additionally, upregulation of the ACSL4-LPCAT3-LOX pathway, iron overload, oxidative stress, fibrosis, and decreased endothelial and smooth muscle cell numbers were observed in the corpus cavernosum of DMED group. Meanwhile, the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway was inhibited, and the Ras homolog gene family member A (RhoA)/Rho-associated protein kinase (ROCK) pathway was promoted in DMED rats. The above histologic alterations and related molecular changes were alleviated after GPX4-LV injection. The results revealed that GPX4 improved erectile function by modulating ferroptosis during DMED progression. This finding is of paramount significance in deciphering the molecular mechanism of hyperglycemia-induced ferroptosis, thereby providing a prospective target for preventing the development of DMED.

Silencing myostatin increases area fraction of smooth muscle in the corpus cavernosum of pigs

Myostatin (MSTN), an inhibitor of skeletal muscle growth, is also expressed in penile smooth muscle; however, it is unclear whether MSTN plays an inhibitory role in penile smooth muscle growth. We investigated the role of MSTN in the smooth muscle of the penile corpus cavernosum of pigs using MSTN homozygous mutant knockout (KO) and wild type (WT) pigs (n = 4 in each group). The mean of area fraction (%) of smooth muscle in the penile corpus cavernosum was 65.9 % ± 1.79 in the KO and approximately 41.7 % ± 5.39 in the WT (P < 0.001). KO pigs showed significantly increased expression of smooth muscle-specific genes, including smooth muscle protein 22 (TAGLN) (6.62-fold), smooth muscle myosin heavy chain (MYH11) (2.41-fold), myocardin (MYOCD) (3.05-fold), and serum response factor (SRF) (4.95-fold), and decreased expression of vimentin (VIM) (1.36-fold). Immunofluorescence staining and Western blotting showed smooth muscle-specific expression of α-smooth muscle actin (SMA) and calponin was higher in KO pigs (P < 0.05) than in WT pigs. KO pigs had less fat deposition inside the corpus cavernosum, and showed downregulation of adiponectin (ADIPOQ) and fatty acid synthase (FASN) (2.5-fold and 1.9-fold loss, respectively). In vitro experiments showed MSTN interference promoted corporal smooth muscle cell growth and expression of smooth muscle-specific markers, whereas it downregulated the expression of fat-specific genes, ADIPOQ and FASN. MSTN inhibition could promote smooth muscle growth and decrease fat deposition in the corpus cavernosum. MSTN, thus, could be a possible target for the treatment of smooth muscle dystrophy-related disorders such as erectile dysfunction.

Ferroptosis is involved in corpus cavernosum smooth muscle cells impairment in diabetes mellitus-induced erectile dysfunction.

Erectile dysfunction (ED) is a common andrological disorder that tends to afflict diabetic patients, among others. Pharmacological therapy of diabetes mellitus-induced ED (DMED) is ineffective, as it is linked with smooth muscle cell loss in the corpus cavernosum. Ferroptosis is a recently identified kind of cell death evoked by lipid peroxidation, and it is connected with a number of diabetic complications. To investigate the role of ferroptosis in DMED. We established the rat model of DMED and conducted a combined analysis of RNA sequencing (RNA-seq) and Gene Expression Omnibus (GEO) data to identify differentially expressed genes (DEGs). Next, DMED disease targets were determined by cross-referencing DEGs and DMED-related genes in the DisGeNET, GenCLiP3, and GeneCards databases. Additionally, these targets were analyzed using "clusterProfiler" in R utilizing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations. Immunohistochemistry (IHC) staining of rat penile tissues was used to validate several targets. Notably, the Cell Counting Kit-8 assay, Western blotting, oxidative stress (OS) level, and iron concentration were tested in corpus cavernosum smooth muscle cells (CCSMCs) stimulated with high glucose (HG), and treated with Ferrostatin-1 (Fer-1). Sixty-nine disease targets of DMED were identified. According to KEGG analysis, these targets were primarily enriched in the ferroptosis pathway. Additionally, IHC results revealed that the expression of GPX4, SLC7A11, and ACSL4 was deregulated in the DMED group compared to the control group. Significantly, HG decreased cell viability and increased OS and iron levels in CCSMCs, which could be reversed by Fer-1 treatment. Our study revealed that ferroptosis may indeed exist in DMED. GPX4, SLC7A11, and ACSL4 all have a role in controlling the viability of CCSMCs, making them potential therapeutic targets.

A comprehensive analysis on the relationship between BDE-209 exposure and erectile dysfunction

Decabromodiphenyl ether (mainly BDE-209) is a commonly used brominated flame retardant in various industrial products. Although its damage to the reproduction system has been established, its effect on erectile function remains unclear. The present study investigated whether BDE-209 induced erectile dysfunction in male SD rats and the underlying mechanisms. Pubertal male rats were exposed to BDE-209 orally (0, 5, 50, and 500 mg/kg/day) for 28 days and the ICP (intracavernous pressure) and MAP (mean arterial pressure) were measured. After the rats were euthanized, the fibrosis and apoptosis levels were evaluated. Additionally, the endothelial function of the rat vascular endothelium cells and the human umbilical vein endothelial cells were impaired after treatment with 50 μM and 100 μM BDE-209. Moreover, the bioinformatics based on CTD database and ChIP-X Enrichment Analysis, version 3 (ChEA3) and molecular docking analysis demonstrated that 5 transcription factors (NFKB1, NR3C1, E2F5, REL, IRF4) might regulate endothelial function by affecting the expression of interactive genes (BCL-2, CAP3, CAT, TNF, MAPK1, and MAPK3). In summary, the present study demonstrated that BDE-209 might affect downstream interactive genes by binding to transcription factors, leading to corpus cavernosum endothelial dysfunction, thus contributing to erectile dysfunction in rats.

Penile Girth Enhancement Using Amniotic Membrane in a Rabbit Model: A stereological study.

This study aimed to evaluate the efficacy of penile girth enhancement (PGE) using amniotic membrane (AM) as a graft in a rabbit model. Additionally, quantitative histological data of the structure of the penis were obtained by stereological studies. This study was conducted at the Histomorphometry and Stereology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran. In this study, 20 adult male rabbits of similar age and weight were allocated to two groups: sham surgery and surgery+AM. Both groups underwent surgery in which a longitudinal I-shaped midline incision was made in the tunica albuginea on the dorsal surface of the penis. The surgery+AM group underwent PGE using AM as a graft. The penile length and mid circumference were measured using a vernier caliper before and two months after the surgery. The mean total volume and diameter of the penis significantly increased in the surgery+AM group (P <0.03 and P <0.04, respectively). On stereological evaluation, a significant increase in the mean volumes of the tunica albuginea and corpora cavernosa was observed in the surgery+AM group compared to the sham group (P <0.01 and P <0.03, respectively). Additionally, the mean volume densities of the collagen bundles, muscle fibres, cavernous sinuses, and the total number of fibroblasts and smooth muscle cells increased in the surgery+AM group compared to the sham group (P <0.05 each). No infections, bleeding or other complications were observed. The use of AM as a graft is a method that shows promising results for material use in penile enhancement. Thus, it may be considered for PGE in the future.

Haptoglobin treatment contributes to regulating nitric oxide signal and reduces oxidative stress in the penis: A preventive treatment for priapism in sickle cell disease.

Background: In sickle cell disease (SCD), reduced bioavailability of endothelial NO and cGMP results in reduced expression of phosphodiesterase type 5 (PDE5), thus impairing the penile erection control mechanism and resulting in prolonged penile erection (priapism). In SCD, reduced NO bioavailability is associated with excess plasma hemoglobin due to intravascular hemolysis and increased oxidative stress. Haptoglobin is the plasma protein responsible for reducing plasma hemoglobin levels, but in SCD, haptoglobin levels are reduced, which favors the accumulation of hemoglobin in plasma. Therefore, we aimed to evaluate the effects of haptoglobin treatment on functional and molecular alterations of erectile function, focusing on the contractile and relaxant mechanisms of corpus cavernosum (CC), as well as oxidative stress. Methods: SCD mice were treated with haptoglobin (400 mg/kg, subcutaneous) or vehicle of Monday, Wednesday and Friday for a period of 1 month. Corpus cavernosum strips were dissected free and placed in organ baths. Cumulative concentration-response curves to the acetylcholine, sodium nitroprusside, phenylephrine and KCL, as well as to electrical field stimulation (EFS), were obtained in CC. Protein expressions of eNOS, phosphorylation of eNOS at Ser-1177, nNOS, PDE5, ROCK1, ROCK2, gp91phox, 3-nitrotyrosine, and 4-HNE were measured by western blot in CC. Results: Increased CC relaxant responses to acetylcholine, sodium nitroprusside and electrical-field stimulation were reduced by haptoglobin in SCD mice. Reduced CC contractile responses to phenylephrine and KCl were increased by haptoglobin in SCD mice. Haptoglobin prevented downregulated eNOS, p-eNOS (Ser-1177), PDE5, and ROCK2 protein expressions and reduced protein expressions of reactive oxygen species markers, NADPH oxidase subunit gp91phox, 3-nitrotyrosine and 4-HNE in penises from SCD mice. Haptoglobin treatment did not affect ROCK1 and nNOS protein expressions in penises from SCD mice. Basal cGMP production was lower in the SCD group, which was normalized by haptoglobin treatment. Conclusion: Treatment with haptoglobin improved erectile function due to up-regulation of eNOS-PDE5 expression and down-regulation of the gp91phox subunit of NADPH oxidase and oxidative/nitrosative stress in the penises of SCD mice. Treatment with haptoglobin also increased contractile activity due to up-regulation of ROCK2. Therefore, haptoglobin treatment may be an additional strategy to prevent priapism in SCD.

Distal vaginal atresia: a report of a rare type found a late-term fetus and its histological comparison with the normal pelvis.

Solitary distal vaginal atresia is generally caused by a transverse septum or an imperforate hymen. We found a novel type of distal vaginal atresia in a late-term fetus (gestational age approximately 28 weeks) in our histology collection. This fetus had a vaginal vestibule that was closed and covered by a thick subcutaneous tissue beneath the perineal skin in the immediately inferior or superficial side of the imperforate hymen. The uterus, uterine tube, anus, and anal canal had normal development. The urethral rhabdosphincters were well-developed and had a normal topographical relationship with the vagina, but the urethrovaginal sphincter was absent. Thus, vaginal descent seemed to occur normally and form the vestibule. However, the external orifice of the urethra consisted of a highly folded duct with hypertrophied squamous epithelium. Notably, the corpus cavernosum and crus of the clitoris had poor development and were embedded in the subcutaneous tissue, distant from the vestibule. Normally, the cloacal membrane shifts from the bottom of the urogenital sinus to the inferior aspect of the thick and elongated genital tubercle after establishment of the urorectal septum. Therefore, we speculate there was a failure in the transposition of the cloacal membrane caused by decreased elongation of the genital tubercle. The histology of this anomaly strongly suggested that the hymen does not represent a part of the cloacal membrane, but is instead a product that appears during the late recanalization of the distal vagina after vaginal descent. The transverse septum was also likely to form during this recanalization.

Intravascular hemolysis leads to exaggerated corpus cavernosum relaxation: Implication for priapism in sickle cell disease

Patients with sickle cell disease (SCD) display priapism. Clinical studies have shown a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD. However, there are no experimental studies that show that intravascular hemolysis promotes alterations in erectile function. Therefore, we aimed to evaluate the corpus cavernosum smooth muscle relaxant function in a murine model that displays intravascular hemolysis induced by phenylhydrazine (PHZ), as well as the role of intravascular hemolysis in increasing the stress oxidative in the penis. Corpus cavernosum strips were dissected free and placed in organ baths. Acetylcholine and electrical field stimulation (EFS)-induced corpus cavernosum relaxations in vitro were obtained. Increased corpus cavernosum relaxant responses to acetylcholine and EFS were observed in the PHZ group. Protein expression of heme oxygenase-1 increased in the corpus cavernosum of the PHZ group, but PDE5 protein expression was not modified. Preincubation with the heme oxygenase inhibitor 1J completely reversed the increased relaxant responses to acetylcholine and EFS in PHZ mice. Protein expression of NADPH oxidase subunit gp91phox, 3-nitrotyrosine, and 4-hydroxynonenal increased in the corpus cavernosum of the PHZ group, suggesting a state of oxidative stress. Basal cGMP production was lower in the PHZ group. Our results show that intravascular hemolysis promotes increased corpus cavernosum smooth muscle relaxation associated with increased HO-1 expression, as well as increased oxidative stress associated with upregulation of gp91phox expression. Moreover, our study supports clinical studies that point to a strong positive correlation between priapism and high levels of intravascular hemolysis in men with SCD.

A Preliminary Study of Constructing the Tissue-Engineered Corpus Cavernosum With Autologous Adipose Stem Cells In Vivo.

IntroductionThe autologous skin flap is still the mainstream method for penile reconstruction, but it is very difficult to reconstruct a functional corpus cavernosum. Tissue engineering provides a new idea aiming to restore the damaged or absent corpus cavernosum.AimTo assess the feasibility of constructing the tissue-engineered corpus cavernosum with autologous adipose stem cells in a rabbit model.MethodsA total of 30 New Zealand male white rabbits. Among them, 20 rabbits were used to obtain the original corpus cavernosum which were used to prepare the acellular corporal scaffolds (ACSs). The others were used for acquiring autologous adipose stem cells (ADSCs) and constructing tissue-engineered corpus cavernosum in vivo.OutcomeACSs were obtained from rabbit penile tissues through an established decellularization procedure. Rabbit autologous ADSCs as seed cells were harvested and expanded. The ADSCs seeded and unseeded ACSs were implanted back into the intramuscular and subcutaneous site in vivo, and the tissue-engineered corpus cavernosum was harvested and analyzed with gross morphology, histological staining, and real-time PCR assay after 1, 3, and 6 months.ResultsACSs were successfully prepared. The cell non-cytotoxicity and integrity of micro-architecture of ACSs was confirmed in vitro. The cell-seeded scaffold in the intramuscular group was considered as the better strategy for constructing the tissue-engineered corpus cavernosum compared with the other groups. Some α-SMA and CD31 positive cells were detected and identified by immunofluorescent staining and real-time PCR assay in the tissue-engineered corpus cavernosum.Clinical TranslationThis study provides a new method for constructing the tissue-engineered corpus cavernosum.Strengths and LimitationsFirst, it is urgent to improve the transformation rate of the endothelial cells and smooth muscle cells from ADSCs. Second, the scaffold harvested in this study was not a complete matrix. Third, further study is needed to explore the potential mechanism of which scaffolds are more suitable for living in intramuscular rather than subcutaneous environment.ConclusionIn this study, we used the autologous ADSCs as seed cells, the acellular corpus cavernosum as scaffolds, and implanted the grafts back into the rabbit model to preliminarily construct the tissue-engineered corpus cavernosum. This study would provide help for further development in tissue-engineered corpus cavernosum.Cao Z, Liu L, Jiao H, et al. A Preliminary Study of Constructing the Tissue-Engineered Corpus Cavernosum With Autologous Adipose Stem Cells In Vivo. Sex Med 2022;10:100563.

Human umbilical cord mesenchymal stem cells ameliorate erectile dysfunction in rats with diabetes mellitus through the attenuation of ferroptosis

BackgroundErectile dysfunction (ED), as one of the most prevalent consequences in male diabetic patients, has a serious impact on men's physical and mental health, and the treatment effect of diabetic mellitus erectile dysfunction (DMED) is often worse. Therefore, the development of a novel therapeutic approach is urgent. As stem cells with high differentiation potential, human umbilical cord mesenchymal stem cells (HUCMSCs) have been widely used in the treatment of diseases in other systems, and are expected to be a promising strategy for the treatment of DMED. In this study, we investigated the role of HUCMSCs in managing erectile function in rat models of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) and compared the effects of two different injection methods.MethodsT1DM and T2DM ED rats were given labelled HUCMSCs by corpus cavernosum injection and tail vein injection, respectively. ICP and MAP were monitored simultaneously by electrical stimulation four weeks after injection to indicate the erectile function of rats. To track the development and colonisation capabilities of stem cells, we performed EdU assay with penile tissue. The histological changes of the penis were observed by hematoxylin–eosin staining, and Masson’s trichrome staining was conducted to evaluate the smooth muscle content and the degree of fibrosis in the rat penis. Then, we employed specific kits to measure the level of NO, cGMP, MDA, SOD and Fe in penis. Electron transmission microscopy was implemented to observe morphology of mitochondria. Besides, western blot and immunofluorescence staining were performed to demonstrate the expression of ferroptosis-related genes.ResultsWe found that HUCMSCs improved erectile function in T1DM and T2DM ED rats, with no difference in efficacy between corpus cavernosum injection and tail vein injection. The EdU assay revealed that only a tiny percentage of HUCMSCs colonised the corpus cavernosum, while smooth muscle in the penis expanded and collagen decreased following HUCMSC injection. Moreover, the levels of oxidative stress in the penis of the rats given HUCMSCs were dramatically reduced, as was the tissue iron content. HUCMSCs normalised mitochondrial morphology within corpus cavernosum smooth muscle cells (CCSMCs), which were characteristically altered by high glucose. Furthermore, the expression of ferroptosis inhibitory genes SLC7A11 and GPX4 was obviously elevated in CCSMCs after stem cell management, but the abundances of ACSL4, LPCAT3 and ALOX15 showed the polar opposite tendency.ConclusionsHUCMSCs can effectively and safely alleviate erectile dysfunction in T1DM and T2DM ED rats, while restoring erectile function by attenuating diabetes-induced ferroptosis in CCSMCs. Additionally, this study provides significant evidence for the development of HUCMSCs as a viable therapeutic strategy for DMED.

Male Perineal Carcinoma: Experience in 4 Cases and Literature Review

Perineal carcinoma of unknown origin is a rare and aggressive disease, so an early diagnosis and adequate treatment are essential to prevent its progression. We report the first series of cases of perineal carcinoma of unknown origin: (I) a 62-year-old male patient being followed up for a urethral stricture treated with periodic dilations with subsequent development of perineal abscesses and perineal carcinoma; (II) a 67-year-old male patient who consults for urinary discomfort associated with a perineal abscess. Recurrence of the abscess in the first month revealed the presence of an underlying perineal carcinoma; (III) a 78-year-old male patient that underwent urethroplasty with graft with subsequent regimen of periodical dilations. Recurrent formation of perianal abscesses revealed the presence of an underlying perineal carcinoma; and (IV) a 78-year-old male patient with history of in situ penile carcinoma treated by glans resurfacing. He consulted for penile pain, and imaging tests revealed a perineal abscess adjacent to the left corpus cavernosum. The core needle biopsy revealed a squamous cell carcinoma. Penile exploration and negative glans biopsy ruled out possible recurrence of penile carcinoma. The form of presentation of the disease has been very similar in all patients, demonstrating the presence of perineal abscess in all cases. Two patients had inguinal lymph node disease at diagnosis. All patients were treated by surgery, and three of them required adjuvant systemic treatment. Surgery combined with systemic treatment is probably the best option if the patient's conditions allow it.

Comparison of preoperative penile elastographic ultrasound findings and pathological tissue results of patients implemented with penile prosthesis.

Histopathological analysis of the relationship between penile elastography and erectile dysfunction. 12 patients who applied to our clinic for erectile dysfunction in the last 1year and accepted this study were included. Preoperative two-dimensional shear wave elastography imaging was performed in 12 patients and recorded in the Pascal (kPa) unit. Approximately 0.5 × 0.5 × 0.5cm tissue samples were taken from the right and left cavernous tissue during penile prosthesis implantation operation. Tissue samples were sent to the pathology department. The percentage of the area covered by muscle fibers and elastic fibers in the corpus cavernosum was noted semi-quantitatively (ratio of muscle fibers and cavernous body elastic fiber score). All data obtained were compared with each other. Cavernous body elastic fiber score data(Grouped Score 1, 2 and 3) and percentage of cavernous body muscle fibers data (Grouped %10, %20, %30… %100) were compared with Shear wave elastography data (kPa). The results were not statistically significant according to the Kruskal Wallis Test. Cavernous body elastic fiber score and the percentage of cavernous body muscle fibers were also compared, it was not statistically significant according to the Kruskal Wallis test and Spearman's correlation test. Penile shear wave elastography can be used clinically to quantitatively assess the amount of smooth muscle cells and elastic fibers in the penis, but it deserves to be studied with a larger number of patients and a more specific interpretation of the pathology preparation.

Treatment of a stallion for penile deviation caused by haemorrhage into the corpus cavernosum penis

SummaryA 19‐year‐old Thoroughbred stallion developed severe curvature of its penis, preventing intromission, after breeding a mare. The cause of the curvature was found, during ultrasonographic examination of the penis, to be rupture of the trabeculae on the left side of the corpus cavernosum penis (CCP) between the cul de sac of the external preputial cavity and the scrotum, resulting in the formation of a seroma. Aspiration of the seroma performed 13 days after injury, with the horse anaesthetised, largely resolved the deviation. A complication of treatment was excessive belling of the glans penis during erection, which may have been the result of a temporary shunt created between the CCP and the corpora spongiosum penis (CSP) by inadvertently passing the spinal needle used to aspirate the seroma through the CSP. Excessive belling resolved after 3 weeks.