Application of Botulinum Neurotoxin in Male Sexual Dysfunction: Where Are We Now?

INTRODUCTION: Botulinum neurotoxin (BoNT) is a recognized therapeutic agent of modern medical care, routinely used to treat medical conditions affecting a variety of organ systems including the musculoskeletal, integumentary, and urological domains. Ongoing research is exploring BoNT's potential role as a therapeutic agent for a variety of male sexual pathologies. OBJECTIVE: To review and analyze the literature regarding BoNT as a treatment option for male sexual dysfunction. METHODS: A PubMed search was performed for English-language articles in peer-reviewed journals between 1970 and 2019 (with one article from 1897). Relevant articles referenced within these texts were also included. One article did not have an accompanied English full-text available. The following search terms were used: "Botox", "Botulinum toxin", "Botulinum toxin A", "Onabotulinum A", "Abobutlinum A", "BoNT", "BoNT-A", "Male sexual health", "Male sexual pathology", "Peyronie's disease", "Premature ejaculation", "Scrotal Pain", "Penile Retraction", "Scrotox", "Erectile Dysfunction", and "Botox in Urology". RESULTS: There is interest in the potential role of BoNT in the treatment of male sexual pathologies. We identified studies that used BoNT to treat chronic scrotal content pain, premature ejaculation, erectile dysfunction, Peyronie's disease, penile retraction, and more. However, despite preclinical/clinical data indicating some potential efficacy and safety in these settings, a lack of robust clinical trial data has resulted in no current Food and Drug Administration-approved indications for the use of BoNT in the treatment of male sexual pathology. As a result, much of the current use of BoNT by today's providers is "off-label," and ongoing clinical trials aim to further elucidate the potential role of this therapeutic agent. CONCLUSION: Current data suggest that BoNT could have a potential role as a treatment option for certain types of male sexual pathologies. However, more randomized controlled trial data regarding its long-term safety and efficacy are necessary before a widespread clinical adoption can take place. Reddy AG, Dick BP, Natale C, et al. Application of Botulinum Neurotoxin in Male Sexual Dysfunction: Where Are We Now?. J Sex Med 2021;9:320-330.

Does Lowering Hemoglobin A1c Reduce Penile Prosthesis Infection: A Systematic Review.

INTRODUCTION: Hemoglobin A1c (HbA1c), a glycated form of hemoglobin, develops when glucose is elevated in the blood. It is used as a marker of how well a diabetic patient has been controlling their blood sugar over the previous 3-4 months. Some use HbA1c as a predictor of infection risk during prosthetic surgery, and many surgeons require patients to lower it preoperatively. OBJECTIVE: This study was designed to comprehensively review the literature relating HbA1c and penile prosthesis (PP). METHODS: A PubMed search of English-language articles identified studies that investigate the relationship between HbA1c levels and PP infection. Studies were only included if they reported the mean HbA1c of all PP patients and compared patients who did/did not develop a prosthetic infection. References from relevant articles are included. RESULTS: A total of 6 studies, 1992-2020, were identified. 2 studies occurred before the advent of antibiotic-enhanced devices in the early 2000s and have limited applicability to the modern era. Of the 4 studies published after, 2 reported a significant difference in mean HbA1c when comparing patients who developed a prosthetic infection and those who did not (9.1% vs 7.5%, P = .000 and 9.5% vs 7.8%, P < .001). The other 2 studies reported no significant difference in mean HbA1c when comparing patients who developed a prosthetic infection and those who did not (7.0% vs 7.6%, P > .05; and 7.6% vs 7.5%, P = .598). CONCLUSION: Current data regarding HbA1c as a predictor of PP infection are inconclusive, with no consensus. HbA1c is increasingly used as a predictor of postsurgical prosthetic infection, with some urologists requiring patients with elevated HbA1c to acutely lower it before elective surgery. While there are a number of established health benefits of controlling elevated blood sugar, larger randomized controlled trials need to validate whether acutely lowering perioperative HbA1c decreases risk of prosthetic infection. Dick BP, Yousif A, Raheem O, et al. Does Lowering Hemoglobin A1c Reduce Penile Prosthesis Infection: A Systematic Review. Sex Med Rev 2021;9:628-635.

Hematopoietic Cell-Expressed Endothelial Nitric Oxide Protects the Liver From Insulin Resistance.

OBJECTIVE: Mice genetically deficient in endothelial nitric oxide synthase (Nos3-/-) have fasting hyperinsulinemia and hepatic insulin resistance, indicating the importance of Nos3 (nitric oxide synthase) in maintaining metabolic homeostasis. Although the current paradigm holds that these metabolic effects are derived specifically from the expression of Nos3 in the endothelium, it has been established that bone marrow-derived cells also express Nos3. The aim of this study was to investigate whether bone marrow-derived cell Nos3 is important in maintaining metabolic homeostasis. Approach and Results: To test the hypothesis that bone marrow-derived cell Nos3 contributes to metabolic homeostasis, we generated chimeric male mice deficient or competent for Nos3 expression in circulating blood cells. These mice were placed on a low-fat diet for 5 weeks, a time period which is known to induce hepatic insulin resistance in global Nos3-deficient mice but not in wild-type C57Bl/6 mice. Surprisingly, we found that the absence of Nos3 in the bone marrow-derived component is associated with hepatic insulin resistance and that restoration of Nos3 in the bone marrow-derived component in global Nos3-deficient mice is sufficient to restore hepatic insulin sensitivity. Furthermore, we found that overexpression of Nos3 in bone marrow-derived component in wild-type mice attenuates the development of hepatic insulin resistance during high-fat feeding. Finally, compared with wild-type macrophages, the loss of macrophage Nos3 is associated with increased inflammatory responses to lipopolysaccharides and reduced anti-inflammatory responses to IL-4, a macrophage phenotype associated with the development of hepatic and systemic insulin resistance. CONCLUSIONS: These results would suggest that the metabolic and hepatic consequences of high-fat feeding are mediated by loss of Nos3/nitric oxide actions in bone marrow-derived cells, not in endothelial cells.

Retained Reservoirs of Inflatable Penile Prosthesis: A Systematic Review of the Literature and a Guide to Perioperative Management.

INTRODUCTION: Retained reservoirs can be a complex problem for clinicians who manage patients with inflatable penile prostheses (IPPs). Although the general safety of retained reservoirs is well documented, data on the long-term outcomes of these foreign bodies is scarce. In recent years, complications associated with retained reservoirs and the subsequent management of these cases have become more recognized. AIM: To review, analyze, and summarize the concept of retained reservoirs and their associated complications with retained reservoirs and to provide a guide for management of complicated retained reservoir patients. METHODS: We performed a systematic review of the PubMed database on retained reservoir-related complications and perioperative management. MAIN OUTCOME MEASURES: We reviewed all publications that detailed complications associated specifically with retained penile prosthesis reservoirs and analyzed perioperative strategies used by providers. Any publication outlining IPP reservoir-related complication(s) stemming from a reservoir that was part of a functioning IPP was excluded. RESULTS: Although the risk is low, serious complications can and do arise from retained reservoirs. To properly manage these patients, clinicians must have knowledge of the prosthetic history and maintain a low threshold for obtaining cross-sectional imaging. By using methodical perioperative planning, the need for reintervention in patients with complications can be reduced, and improved surgical outcomes can be achieved. CONCLUSIONS: The management of retained reservoirs and their complications can be a clinical challenge for prosthetics providers. As such, more data regarding long-term outcomes and management strategies of retained reservoirs are required to better serve this subset of patients with prostheses. Reddy AG, Tsambarlis PN, Akula KP, et al. Retained Reservoirs of Inflatable Penile Prosthesis: A Systematic Review of Literature. Sex Med Rev 2020;8:355-363.

The role of vasodilator-stimulated phosphoprotein (VASP) in the control of hepatic gluconeogenic gene expression.

During periods in which glucose absorption from the gastrointestinal (GI) tract is insufficient to meet body requirements, hepatic gluconeogenesis plays a key role to maintain normal blood glucose levels. The current studies investigated the role in this process played by vasodilatory-associated phosphoprotein (VASP), a protein that is phosphorylated in hepatocytes by cAMP/protein kinase A (PKA), a key mediator of the action of glucagon. We report that following stimulation of hepatocytes with 8Br-cAMP, phosphorylation of VASP preceded induction of genes encoding key gluconeogenic enzymes, glucose-6-phosphatase (G6p) and phosphoenolpyruvate carboxykinase (Pck1), and that VASP overexpression enhanced this gene induction. Conversely, hepatocytes from mice lacking VASP (Vasp-/-) displayed blunted induction of gluconeogenic enzymes in response to cAMP, and Vasp-/- mice exhibited both greater fasting hypoglycemia and blunted hepatic gluconeogenic enzyme gene expression in response to fasting in vivo. These effects of VASP deficiency were associated with reduced phosphorylation of both CREB (a key transcription factor for gluconeogenesis that lies downstream of PKA) and histone deacetylase 4 (HDAC4), a combination of effects that inhibit transcription of gluconeogenic genes. These data support a model in which VASP functions as a molecular bridge linking the two key signal transduction pathways governing hepatic gluconeogenic gene expression.