Intracavernous application of autologous bone marrow stem cells for medical treatment-refractory erectile dysfunction: A case report

Clinical case description: A 61-year-old man with severe erectile dysfunction related to diabetes mellitus of long duration was treated through intracavernous stem cell application. Transplantation of autologous bone marrow stem cells through a single intracavernous injection was performed. Clinical response, Doppler ultrasound of the penis, and adverse events were evaluated during the 50-week follow-up. The highest clinical response was reported at week 12, but it diminished thereafter. At the end of follow-up, ultrasound identified the presence of neovascularization emerging from the cavernous arteries. Relevance: Numerous preclinical trials have demonstrated efficacy and safety, but there is insufficient clinical evidence showing promising results. Clinical implications: No adverse events were detected, and ultrasound revealed hemodynamic changes that were possibly related to the therapy. The source and dosage of stem cells, as well as subsequent therapeutic applications, pose questions that remain to be answered. Conclusions: Stem cell therapy for erectile dysfunction is a field of research that has sparked interest in numerous scientific groups, but clinical experience is still limited.


Introduction
Erectile dysfunction (ED) is a condition of considerable prevalence worldwide, affecting 19.2% of the male population. (1) Currently, first-line treatment for ED consists of phosphodiesterase type 5 (PDE-5) inhibitor use and changes in lifestyle. Intracavernous injection of prostaglandin analogs and penile prosthesis are other available treatment modalities used in cases of severe erectile dysfunction that do not respond to first-line treatment. (2) The inconvenience of those therapeutic modalities lies in the high risk of adverse events, such as local pain and bruising related to continuous prostaglandin analog injections, infections, and complications related to the surgical procedure of penile prosthesis. Stem cell (SC) therapy appears to be a promising option in that group of patients. (3,4) We present our experience of a patient with medical treatment-refractory ED, who rejected second and third-line therapy, and instead, opted for transfusion with autologous bone marrow total nucleated cells at our hospital.

Clinical case
A 61-year-old man sought medical attention at the Urology Department, complaining of a Total testosterone was 552 ng/dL (normal range of 240-950 ng/dL) and free testosterone was 8.1ng/dL (normal range of 3.67-13.9 ng/dL). (5) Infectious diseases (human immunodeficiency virus, hepatitis B, hepatitis C, and syphilis) were ruled out by standard methods.  Penile implant was proposed but the patient rejected the procedure due to its surgical risks and high cost.  Table 1. After asepsis and local anesthesia, 4 mL of the sample was injected at the external surface of each cavernous body in the proximal third of the flaccid penis. The penile root was clamped for 2 minutes. No complications were reported. The entire procedure was performed, and the patient was discharged, both on the same day.

Follow-up Assessment
The current treatment for ED, adverse effects, the Erection Hardness Score (EHS), and the IIEF-5 were evaluated at each follow-up appointment, scheduled at weeks 4, 8, 12, 16, 20, 32, and 50 (Figure 2). CDUS was performed prior to SC transplantation (baseline) at week 12 and week 50 ( Figure   3). Detailed data obtained in the imaging studies are shown in Table 2.   week.
The highest scores during follow-up were at week 12, with an IIEF-5 score of 21 pts and an EHS of 4, classified as mild erectile dysfunction that was responsive to PDE-5 inhibitors.
After week 12, the quality of the erections gradually declined. However, good response to PDE-5 inhibitors persisted over time.

Discussion
We detected a peak response to therapy at Four diabetic patients with refractory ED were included. Two consecutive intracavernous autologous BM mesenchymal SCs injections were performed. A significant improvement on the IIEF-15 and EHS scores were reported and no significant adverse effects were found. (10) The presence of prominent helicine arteries with a high PSV was an outcome not described in previous clinical trials. However, those findings were reported in several preclinical trials performed on rat models. (6)(7)(8)(9) Those multiple tortuous vessels branch off at the cavernous artery and open directly into the cavernous spaces, acting as resistance arteries.
The importance of those vascular structures is in the mechanism of penile resistance of the arterial smooth muscle. They act as sphincters and regulate blood flow between the systemic circulation and the cavernous sinusoids, an essential phenomenon for erectile function. (11) The role of SCs in the management of ED is