Stem-Cell, Shockwave, and Platelet Rich Plasma Therapy for the Treatment of Erectile Dysfunction and Peyronie's Disease: A Survey of Clinics Across the USA.

OBJECTIVE: To identify clinics offering off-label therapies for erectile dysfunction (ED) and Peyronie's disease (Pyd) including stem cell, platelet-rich plasma (PRP), and shockwave therapy and to determine the transparency they provided to patients inquiring about these treatment modalities. METHODS: Clinics were identified in different regions in the US using a systematic search on online website directories and were approached by asking a series of standardized questions regarding the cost of treatment, duration of therapy, the medical staff involved, and patient outcome data. A total of 26 clinics were surveyed for stem cell therapy, 26 for PRP treatment, and 27 for shockwave therapy. RESULTS: Of the 79 clinics contacted, 93.7% provided some answers to the questions we asked, with a majority offering treatments for both ED and Pyd. The cost of treatment varied widely between clinics. The average cost per stem cell therapy injection was $5291, PRP per injection was $1336, and shockwave therapy per session was $413. A physician was involved in 67% of treatments, and only 6 of 79 clinics reported that a urologist was involved. Over 75% of the clinics reported patient satisfaction following treatment. Durability of benefits to patients ranged from months to years according to the clinics' reports. CONCLUSION: Our data not only demonstrate the widespread use of off-label therapies for ED and PyD across the United States but also the lack of scientific data to support the claims made to patients. This study highlights the need for more oversight and standardization in novel regenerative therapies for ED and PyD.

Advanced Paternal Age and Sperm DNA Fragmentation: A Systematic Review.

PURPOSE: Male ageing is often associated with defective sperm DNA remodeling mechanisms that result in poorly packaged chromatin and a decreased ability to repair DNA strand breaks. However, the impact of advanced paternal age on DNA fragmentation remains inconclusive. The aim of the present systematic review was to investigate the impact of advancing paternal age (APA) on DNA fragmentation. MATERIALS AND METHODS: We conducted a thorough search of listed publications in Scopus, PubMed, and EMBASE, in accordance with the PRISMA guidelines. RESULTS: We identified 3,120 articles, of which nineteen were selected for qualitative analysis, resulting in a sample of 40,668 men. Of the 19 articles evaluating the impact of APA on DFI% (DNA fragmentation Index) included, 4 were on Normozoospermic and subfertile men, 3 on normozoospermic, Oligoasthenoteratozoospermic and Teratozoospermic, 6 on fertile and infertile men, 4 on just infertile men, and 2 evaluated a general population. Seventeen of the ninrnteen studies demonstrated APA's effect and impact on DFI%. CONCLUSIONS: Although there was no universal definition for APA, the present review suggests that older age is associated with increased DFI. In elderly men with normal semen parameters, further studies should be performed to assess the clinical implications of DFI, as a conventional semen analysis can often fail to detect an etiology for infertility.

Impact of the SARS-CoV-2 virus on male reproductive health.

The coronavirus 2019 (COVID-19) pandemic caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to more than 160 million infections and 3.5 million deaths globally. Men are disproportionately affected by COVID-19, having more severe disease with higher mortality rates than women. Androgens have been implicated as the underlying cause for more severe disease, as the androgen receptor has been noted to upregulate the cell surface receptors that mediate viral cell entry and infection. Unfortunately, despite testosterone's potential role in COVID-19 prognosis, androgen deprivation therapy is neither protective nor a treatment for COVID-19. Interestingly, the male reproductive organs have been found to be vulnerable in moderate to severe illness, leading to reports of erectile dysfunction and orchitis. COVID-19 viral particles have been identified in penile and testis tissue, both in live patients who recovered from COVID-19 and post mortem in men who succumbed to the disease. Although sexual transmission remains unlikely in recovered men, moderate to severe COVID-19 infection can lead to germ cell and Leydig cell depletion, leading to decreased spermatogenesis and male hypogonadism. The objective of this review is to describe the impact of SARS-CoV-2 on male reproductive health. There are still many unanswered questions as to the specific underlying mechanisms by which COVID-19 impacts male reproductive organs and the long-term sequelae of SARS-CoV-2 on male reproductive health.

Elevated sperm DNA fragmentation does not predict recurrent implantation failure.

In this study, we sought to determine whether sperm DNA fragmentation (DFI%) and high DNA stainability (HDS%) evaluated by sperm chromatin structure assay (SCSA) predict recurrent implantation failure (RIF) or pregnancy rate. A retrospective study was performed of consecutive cycles of ICSI treatment from 2009 to 2018. A total of 386 couples that underwent 1,216 frozen embryo transfer (FET) cycles were analysed. Mean female and male age was 34 ± 3.6 years and 37.3 ± 6.6 years, respectively, and a median total motile sperm count (TMSC) was 43.5 [9.9-105.5] million. Overall median DFI% and HDS% was 12 [7.1-18.9] and 9.6 [6.5-14.4] respectively. On multivariable analysis, DFI% and HDS% were not associated with RIF (DFI%: OR = 1.01, 95% CI: 0.98-1.04, p = .414; HDS%: OR = 0.97, 95% CI: 0.94-1.01, p = .107) or IVF success, defined as clinical pregnancy (DFI%: OR = 1.00, 95% CI: 0.99-1.01, p = .641; HDS%: OR = 1.01, 95% CI: 0.99-1.02, p = .565). We found that neither DFI% or HDS%, as assessed by SCSA, were predictive of RIF or pregnancy rate. This finding suggests that sperm DNA fragmentation does not predict RIF or pregnancy rate.

Evaluation of SARS-CoV-2 in Human Semen and Effect on Total Sperm Number: A Prospective Observational Study.

PURPOSE: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has created a surge of research to help better understand the breadth of possible sequelae. However, little is known regarding the impact on semen parameters and fertility potential. We sought to investigate for presence of viral RNA in semen of men with SARS-CoV-2 infection and to evaluate its effect on semen parameters in ejaculate. MATERIALS AND METHODS: We prospectively recruited thirty men diagnosed with acute SARS-CoV-2 infection using real-time reverse transcriptase polymerase chain reaction (RT-PCR) of pharyngeal swab specimens. Semen samples were collected from each individual using mailed kits. Follow-up semen samples were done with mailed kits or in-person in office setting. Semen analysis and PCR was performed after samples were received. RESULTS: Thirty semen samples from recovered men were obtained 11-64 days after testing positive for SAR-CoV-2 infection. The median duration between positive SAR-CoV-2 test and semen collection was 37 days (interquartile range [IQR]=23). The median total sperm number (TSN) in ejaculate was 12.5 million (IQR=52.1). When compared with age-matched SARS-CoV-2(-) men, TSN was lower among SARS-CoV-2(+) men (p=0.0024). Five men completed a follow-up sperm analysis (median 3 months) and had a median TSN of 18 million (IQR=21.6). No RNA was detected by means of RT-PCR in the semen in 16 samples tested. CONCLUSIONS: SARS-CoV-2 infection, though not detected in semen of recovered men, can affect TSN in ejaculate in the acute setting. Whether SARS-CoV-2 can affect spermatogenic function long-term remains to be evaluated.

Androgenization in Klinefelter syndrome: Clinical spectrum from infancy through young adulthood.

Klinefelter syndrome (KS) is an uncommon chromosomal disorder in males that has a variable clinical appearance. Classic KS involves an extra X chromosome, (47, XXY), although other variations may exist, including a milder mosaic form as well as multiple extra sex chromosomes with more dramatic phenotypes. KS is underdiagnosed, especially pre-pubertally, owing to a paucity of concrete clinical signs; however, diagnostic rates increase during and after puberty, as the consequences of hypergonadotropic hypogonadism begin to manifest. Testicular failure causing decreased circulating testosterone (T) and germ cell depletion, a hallmark feature in KS, commonly begins shortly after the onset of puberty and leads to the most commonly recognized KS traits: small testes, azoospermia, gynecomastia, decreased facial and pubic hair. While many KS men maintain adequate T levels leading up to young adulthood, some may have lower T levels at an earlier age leading to varied levels of androgenization and clinical KS features. At certain critical time points, absent or decreased T may alter the development of normal male reproductive organs, external genitalia, development of secondary sexual characteristics and spermatogenesis. Testicular failure in utero may lead to ambiguous genitalia, cryptorchidism and/or hypospadias, all of which depend on fetal T production. In the neonatal period and childhood, decreased T levels during the mini-puberty of infancy may negatively impact germ cell differentiation and male neuropsychological development. Finally, decreased T during pubertal and young adulthood can lead to decreased virilization during puberty, eunuchoid skeleton and decreased spermatogenesis. Depending on the timing of the testicular failure, a reproductive window of sperm production may exist to achieve paternity for KS men. The presence or absence of clinical characteristics reflecting decreased androgenization provides an insight to the relative testicular function during these developmental time points for those with KS and contributes to variability within the syndrome.

Clinical Update on Home Testing for Male Fertility.

Male factor infertility accounts for about 50% of the incidence of infertility in couples. In current practice, the men must attend a clinic or hospital facility to provide a semen analysis, which is key to the diagnosis of the male reproductive potential. However, many men are often embarrassed with the process and conventional semen analysis requires complex, labor intensive inspection with a microscope. To mitigate these problems, one of the solutions can be at-home semen analysis. In this review we examine the literature of currently available at home semen analysis test kits, describe their limitations, and compare them to the conventional lab-based methods.

The Effect of Longer-Acting vs Shorter-Acting Testosterone Therapy on Follicle Stimulating Hormone and Luteinizing Hormone.

INTRODUCTION: Testosterone (T) replacement therapy causes suppression of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) that can lead to decrease in semen parameters and possible infertility. Different T formulations may have varying suppression on FSH and LH. OBJECTIVE: To study whether shorter-acting T (multiple daily dosing) has less suppression on FSH and LH serum levels compared with longer-acting T (transdermal gel, injectable). METHODS: A systematic literature search was conducted by following the protocol based on Preferred Reporting Items for Systematic Reviews and Meta-Analysis protocols. We comprehensively reviewed the literature by systematically searching manuscripts indexed in PubMed from 1995 to March 13, 2019 to identify studies reporting changes in FSH and LH in hypogonadal men treated with exogenous T which evaluated the effect of exogenous T on FSH and LH. RESULTS: A total of 8 studies reported the effect of T on FSH and LH in 793 hypogonadal men: 2 used long-acting injectables (enanthate or undecanoate) in a total of 16 men, 5 used intermediate-acting daily topical gels or patches in a total of 471 men, and 1 used short-acting intranasal T (125 µL/nostril, twice a day or three times a day) in 306 men. Long-acting injectables decreased FSH by 86.3%, intermediate-acting daily gels/patches decreased FSH by 60.2%, and short-acting intranasal gel decreased FSH by 37.8%. Long-acting injectables decreased LH by 71.8%, intermediate-acting daily gels/patches decreased LH by 59.2%, and short-acting intranasal gel decreased LH by 47.3%. CONCLUSIONS: Our findings suggest that short-acting T preparations do not decrease serum FSH or LH to the same extent as longer-acting transdermal gels and injectables. However, further clinical trial data are necessary to determine whether the effect of short-acting TRT on gonadotropins translates into similar changes in semen parameters and fertility. Masterson TA, Turner D, Vo D, et al. The Effect of Longer-Acting vs Shorter-Acting Testosterone Therapy on Follicle Stimulating Hormone and Luteinizing Hormone. Sex Med Rev 2021;9:143-148.

Curcumin Supplementation and Endometrial Lining: Examining the Role and Pathophysiology of Use During Frozen-Thawed Embryo Transfer.

Curcumin is a commonly used herbal supplement purported for its antioxidant, anti-inflammatory, and antineoplastic properties. The effects of curcumin supplementation on endometrial lining have been proposed; however, endometrial preparation in the case of frozen-thawed embryo transfer (FET) has not been established. This case series references two scenarios where turmeric was ingested by the patient, and endometrial thickness was subsequently reduced disrupting the FET cycle. Throughout this case series, curcumin's possible interactions with the uterine lining are summarized. Additionally, these cases highlight the importance of physicians' awareness of taking a full history of any herbal remedies or supplements in addition to prescription or over-the-counter medications taken when undergoing treatment for controlled FET cycles or in-vitro fertilization (IVF). To our knowledge, no studies to date have investigated this relationship.

A cross-sectional comparison of secondary polycythemia in testosterone-deficient men treated with nasal testosterone gel vs. intramuscular testosterone cypionate.

INTRODUCTION: Secondary polycythemia is a known adverse effect of testosterone replacement therapy (TRT). Different testosterone formulations are available, with significantly different half-lives, which have varying influences on the development of secondary polycythemia. Herein, we compared the prevalence of secondary polycythemia in testosterone-deficient men treated with intranasal testosterone gel (Natesto®) vs. intramuscular testosterone cypionate (TC) therapy. METHODS: We performed a cross-sectional analysis of secondary polycythemia (hematocrit [Hct] ≥54%) in men who received TRT. We included a total of 60 men: 30 men who received Natesto (4.5% testosterone gel [tid, 5.5 mg/nostril, 11 mg/dose, 33 mg/day]), and 30 who received TC (between 0.5 and 1.0 mL or 100-200 mg intramuscularly weekly). A univariable and multiple regression analysis was performed considering last Hct measurement as the main outcome. The analyzed variables included were age, body mass index (BMI), smoking history, treatment group, and testosterone levels on followup. RESULTS: We identified polycythemia (Hct ≥54%) in 10% (3/30) of men who received TC. Additionally, in men treated with TC, 33.3% (10/30) had a Hct ≥50% during therapy. None of the men who received Natesto had a Hct ≥50% during therapy. On multivariable linear regression analysis, we demonstrated that the use of TC increased Hct by 3.24% (95% confidence interval [CI] 0.74-5.73%, p=0.012) compared to Natesto. CONCLUSIONS: The prevalence of polycythemia in men treated with Natesto was markedly lower compared to the men who received TC therapy.

Sperm DNA fragmentation index and high DNA stainability do not influence pregnancy success after intracytoplasmic sperm injection.

OBJECTIVE: To evaluate the ability of sperm DNA fragmentation index (DFI%) and high DNA stainability (HDS%) to influence the chance of achieving pregnancy in couples undergoing intracytoplasmic sperm injection (ICSI) cycles. DESIGN: A retrospective study evaluating couples that underwent an ICSI cycle between 2009 - 2018. SETTING: High-volume reproductive center. PATIENTS: Consecutive couples who underwent an ICSI cycle and had a semen analysis with subsequent DFI% and HDS% testing, evaluated by Sperm Chromatin Structure Assay (SCSA). INTERVENTIONS: Measurement of DFI% and HDS% prior to ICSI cycle. MAIN OUTCOME MEASURES: To determine whether DFI% or HDS% of sperm was predictive of the number of ICSI cycles until the first clinical intrauterine pregnancy. RESULTS: A total of 550 couples who underwent 1050 ICSI cycles were analyzed. Of those, a total of 330 couples achieved pregnancy. As expected, in couples that achieved pregnancy, females were younger (33.7 ± 3.6 years vs 35.3 ± 3.4 years; p < 0.001) and underwent fewer cycles (2 [1-2] vs 2 [1-3]; p =0.001). Importantly, the DFI% and HDS% were similar between couples who achieved pregnancy (DFI% = 12.9 [8-20]; HDS% = 9.3 [6.1-14.6]) and couples who did not (DFI% =12.2 [7.1-20.2]; HDS% = 9.1 [6.7-14]). A multivariable-adjusted analysis evaluating female age at the first cycle was negatively associated with pregnancy (OR = 0.827, 95% CI: 0.778 - 0.879; p < 0.001). CONCLUSIONS: Neither DFI nor HDS at baseline influence the chances of a couple to achieve pregnancy after ICSI. Increased female age and couples who underwent more ICSI cycles were associated with lower chances of achieving pregnancy.

Use of 4K3D Video Microscope in Male Infertility Microsurgery.

OBJECTIVE: To evaluate a 4K3D video microscope in the operating room of an outpatient surgical center during male infertility microsurgery procedures. DESIGN: Video presentation. SETTING: University of Miami outpatient surgical center. PATIENTS: All patients undergoing microsurgical procedures who signed a written, informed consent for video and audio recording. INTERVENTIONS: vasovasotomy, vasoepididymostomy, varicocele repair, microsurgical testicular sperm extraction. MAIN OUTCOME MEASURES: Operating room times and surgeon fatigue. RESULTS: This video demonstrates the potential advantages of a 4K3D video microscope in the operating room compared to the standard optical operating microscope (SOM), as well as robotic assisted microsurgery. Operating times for all varicocele repair cases performed with the 4k3D video microscope during the 4-week trial period (6), were compared to the 6 most recent varicocelectomies done with a SOM. We observed a decrease in the median operating room times (74.5 minutes vs 96.5 minutes) for those surgeries involving the 4k3D video microscope. Mann Whitney U test was used to compare median operating times, however, because of our small sample size this was not statistically significant (p=0.092) (Figure 1). Additionally, between cases, the transport of microscope from room to room, draping and setup of the 4k3D video microscope required less time and was less strenuous for the OR staff. The 4k3D video microscope allows the surgeon to operate in a more ergonomic position compared to the SOM and comes at a price point which is more reasonable than a surgical robot (DaVinci). CONCLUSION: The 4K3D video microscope offers potential ergonomic and logistical advantages over the SOM and robotically assisted surgery. Future studies with larger sample sizes are needed to evaluate these potential advantages and objectively study the ergonomic improvements that the 4k3D video microscope offers over the SOM.

Factors influencing postmortem disposition of cryopreserved sperm in men undergoing fertility preservation.

OBJECTIVE: To study the factors that influence men's disposition towards post-mortem disposition of their cryopreserved gametes. DESIGN: A retrospective chart review of sperm cryopreservations between June 2016 and January 2020 was performed. All patients ≥ 18 years of age were included. Samples intended for donation or records with an unspecified reason for preservation were excluded. SETTING: A large academic health center. PATIENTS: Participants' (n=217) mean age was 35.8 ± 10.8 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patients' reason for undergoing sperm cryopreservation, method of retrieval, and whether they chose to have the sample preserved or discarded post-mortem. RESULTS: A total of 217 men were analyzed; mean age was 35.8 ± 10.8 years. Of those, 176 (81.1%) men decided to preserve their sperm for a spouse and 41 (18.9%) elected to have the sample discarded when choosing the fate of their cryopreserved sample should they die. There was no significant difference in disposition towards sample fate based on age or method of collection. However, there was a significant difference based on the "reason for cryopreservation" (p = 0.001). We found that compared to patients that underwent sperm cryopreservation due to cancer-related treatments, the patients that underwent sperm banking prior to vasectomy were more inclined to discard the sample (OR = 3.45, 95% CI: 1.16 - 10.27, p = 0.026). Men that collected the sperm as an in vitro fertilization backup were less willing to discard the sample (OR = 0.42, 95% CI: 0.18 - 0.97, p = 0.043). CONCLUSIONS: It appears that men's disposition towards post-mortem disposition of their cryopreserved sperm are influenced by their reason for cryopreservation, rather than their age or method used for collection. As cryopreservation has become more common and affordable, understanding the factors that impact men's disposition towards the post-mortem disposition of the cryopreserved gametes is imperative, as this knowledge has the potential to influence institutional policies and legislation, and may help solve future legal conflicts and ethical dilemmas.

Effect of Natesto on Reproductive Hormones, Semen Parameters and Hypogonadal Symptoms: A Single Center, Open Label, Single Arm Trial.

PURPOSE: To evaluate the effect of short-acting 4.5% nasal testosterone gel (Natesto) on serum testosterone, gonadotropins, total motile sperm count, health related quality of life and sexual function. MATERIALS AND METHODS: This was a single institution, open label, single arm trial conducted between November 2017 and September 2019 at the University of Miami. Men 18 to 55 years old diagnosed with symptomatic hypogonadism (total testosterone less than 300 ng/dl on 2 occasions) were included. Men with azoospermia, vasectomy or a total motile sperm count less than 5 million were excluded. Enrolled patients were treated with Natesto, a short-acting nasal testosterone (125 µl per nostril, 11.0 mg testosterone per dose, TID) for 6 months. RESULTS: In total, 60 men were enrolled in the study. Of these, 44 and 33 patients were evaluated for testosterone at 3 and 6 months, respectively. A total of 31 patients (90.9%) reached a normal testosterone level (greater than 300 ng/dl) at 6 months. Follicle stimulating hormone and luteinizing hormone levels were maintained within the normal range in 81.8% and 72.7% of patients at 6 months, respectively. Total motile sperm count was maintained with total motile sperm count greater than 5 million over the treatment period in 88.4% of men at 3 months and 93.9% at 6 months. There were statistically significant improvements on International Index of Erectile Function sexual desire and overall satisfaction domains at 6 months. CONCLUSIONS: Natesto appears to increase testosterone while maintaining semen parameters in a majority of men. Natesto has the potential to be a safe and effective treatment for men with functional hypogonadism who wish to preserve semen parameters. Long-term studies beyond 6 months are needed before we can safely prescribe nasal testosterone gel for men interested in fertility.

Best practices for infection prevention in penile prosthesis surgery.

PURPOSE OF REVIEW: In this review, we synthesize the most current data on strategies for the prevention and reduction of infections in men undergoing penile prosthesis surgery. We highlight important strategies for preventing infections along every step from patient selection, to the preoperative, intraoperative and postoperative states. RECENT FINDINGS: Over the last decade, significant advances have been made to help minimize penile implant infections, with the most impactful likely being the introduction of antibiotic coated penile implants. Although this has led to infection rates lower than 0.5% being reported in some series, it appears that more virulent organisms are causing a larger share of infections. SUMMARY: The change in the microbiology and persistent occurrence of penile implant infections challenges us to develop strategies to target these organisms by using novel antibiotic mixes for irrigation, dips and implant coatings. Equally important is the continual search to identify patient risk factors for the development of infections and the further optimization of the use of oral and intravenous antibiotics. It is likely we will find inspiration by looking at nonurological surgical specialties where implantation of permanent devices is routine.