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.

Age-dependent effect on contralateral testicular compensation after testicular loss.

OBJECTIVE: To study compensatory changes in testicular growth and the hormonal axis after unilateral orchiectomy in a neonatal, prepubertal, and pubertal/adult murine model. This is the first study to use a neonatal mouse survival surgery model. DESIGN: A laboratory-based study examining a control, neonatal, prepubertal, and pubertal/adult mouse model. SETTING: University-based basic science research laboratory. ANIMALS: Control, neonatal (2-4 days of life), prepubertal (12-21 days of life), and pubertal/adult (42-44 days of life) C57BL/6 mouse models. INTERVENTION: Unilateral orchiectomy in the neonatal, prepubertal, and pubertal/adult mouse models at their respective ages. MAIN OUTCOME MEASURES: Body and testis weight and testicular length in the long axis were measured in a blinded fashion. In a similar way, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone were assessed. RESULTS: Testes from neonatal and prepubertal mice weighed more (110.5, 12.2 and 103.0, 7.2 mg, respectively) than the control mice (91, 11.9 mg). There was no difference between the postpubertal group and the control group. The degree of compensatory hypertrophy was greater in the neonatal group but not in the prepubertal group when compared with the postpubertal group. Differences in follicle-stimulating hormone and testosterone were not statistically significant between the experimental and control arms. LH was significantly elevated in all experimental groups compared with the control. CONCLUSIONS: This is the first study to assess testicular compensatory hypertrophy using a neonatal mouse survival surgery model. Testicular hypertrophy occurs when unilateral loss occurs before puberty, but not in adulthood in mice. Earlier testis loss may contribute to a greater degree of growth. Functionally, the unilateral testis can maintain eugonadal testosterone levels, but higher levels of LH are required after hemicastration to sustain eugonadal testosterone levels.

Comparison of Intratesticular Testosterone between Men Receiving Nasal, Intramuscular, and Subcutaneous Pellet Testosterone Therapy: Evaluation of Data from Two Single-Center Randomized Clinical Trials.

PURPOSE: Testosterone replacement therapy (TRT) can potentially cause decreased spermatogenesis and subsequent infertility. Recent studies have suggested that 17-hydroxyprogesterone (17-OHP) is a reliable surrogate for intratesticular testosterone (ITT) that is essential for spermatogenesis. We evaluated data from two ongoing open-label, randomized, two-arm clinical trials amongst different treatment preparations (Trial I) subcutaneous testosterone pellets (TP) and (Trial II) intranasal testosterone (NT) or intramuscular testosterone cypionate (TC). MATERIALS AND METHODS: Seventy-five symptomatic hypogonadal men (2 serum testosterone <300 ng/dL) were randomized into open label randomized clinical trials. Eligible subjects received 800 mg TP, 11 mg TID NT or 200 mg ×2 weeks TC. 17-OHP and Serum testosterone were evaluated at baseline and follow-up. The primary outcome was changes in 17-OHP. Secondary outcome was changes in serum testosterone. Data was analyzed by two-sample and single-sample t-tests, and determination of equal or unequal variances was computed using F-tests. RESULTS: Median participant age was 45 years old, with overall baseline 17-OHP of 46 and serum testosterone of 223.5 ng/dL. 17-OHP significantly decreased in subjects prescribed long-acting TP or TC. The 4-month change in 17-OHP in the NT group (-33.3% from baseline) was less than the change seen in TC (-65.3% from baseline) or TP (-44% from baseline) (p=0.005). All testosterone formulations increased serum testosterone levels at follow-up, with the largest increase seen in TC (+157.6%), followed by NT (+114.3%) and TP (+79.6%) (p=0.005). CONCLUSIONS: Short-acting nasal testosterone appear to have no impact on serum 17-OHP especially in comparison to long-acting testosterone formulations. All modalities saw significant increases in serum testosterone levels at follow-up. NT and other short acting testosterone formulations may better preserve ITT and be beneficial for hypogonadal men seeking to maintain fertility potential while on TRT.

Prevalence of secondary erythrocytosis in men receiving testosterone therapy A matched-cohort analysis of intranasal gel, injections, and pellets.

INTRODUCTION: Increased hematocrit (HCT) is a common adverse effect in men on testosterone therapy (TTh). We aimed to uncover differences in HCT changes among men receiving different forms of TTh. METHODS: We conducted a single-center, retrospective, matched-cohort study of patients treated for testosterone deficiency (TD) to investigate the effect of three TTh regimens on HCT. We included men who received intranasal testosterone (NT), intramuscular testosterone (TC), or subcutaneous testosterone pellet (TP) regimens between January 2011 and December 2020. We matched treatment cohorts 1:1:1 for age, body mass index (BMI), and history of obstructive sleep apnea (OSA). Those taking TTh for <16 weeks were excluded. Comparison between groups was performed with Mann-Whitney U test, Student's t-test, ANOVA, or Kruskal-Wallis test as appropriate. RESULTS: Seventy-eight matched-cohort individuals with TD received either NT, TC, or TP. The most common TD symptoms prior to initiation of TTh were erectile dysfunction (38%), low libido (22%), and lack of energy (17%). Baseline serum testosterone and HCT were higher in NT recipients (p<0.05). As expected, all men receiving TTh were found to have increased serum testosterone levels at followup (p<0.001). Relative to their respective baselines, men receiving TC experienced the greatest increase in serum testosterone (240.8 ng/dL to 585.5 ng/dL), followed by NT (230.3 ng/dL to 493.5 ng/dL) and TP (210.8 ng/dL to 360.5 ng/dL) (all p<0.001). TC and TP were associated with significant increases in HCT (4.4% and 1.7%) while NT was associated with a decrease in HCT (-0.8%) at 16-week followup. CONCLUSIONS: When controlled for age, BMI, and OSA, men receiving NT experienced decreased HCT compared to TC or TP at 16-week followup. Intranasal testosterone, while able to increase serum testosterone levels to reference range, does not appear to have a significant impact on HCT compared to the longer-acting forms of TTh.

Efficacy and safety outcomes of a compounded testosterone pellet versus a branded testosterone pellet in men with testosterone deficiency: a single-center, open-label, randomized trial.

Background: Testosterone deficiency (TD) is a prevalent condition, especially in men ≥45 years old, and testosterone therapy (TTh) can improve the quality of life in these patients. Aim: To evaluate the safety profile of compounded subcutaneous testosterone pellets and to compare the efficacy between compounded and market brand testosterone pellets for TTh: E100 (Empower Pharmacy) and Testopel (Food and Drug Administration approved), respectively. Methods: This was a prospective, phase 3, randomized, noninferiority clinical trial. We enrolled 75 men diagnosed with TD and randomized them 1:1 to a market brand group and a compounded pellet group. The patients were implanted with their respective testosterone pellets: Testopel (10 pellets of 75 mg) and E100 (8 pellets of 100 mg). Outcomes: We evaluated adverse events after implantation and followed men at 2, 4, and 6 months for morning laboratory levels (prior to 10 am): serum testosterone, estradiol, hematocrit, and prostate-specific antigen. Results: After randomization, 33 participants were enrolled in the Testopel arm and 42 in the E100 arm. Serum testosterone levels were similar between the groups at 2, 4, and 6 months, with most men (82%) dropping to <300 ng/dL by the end of the trial. Adverse events were also similar, such as elevations in prostate-specific antigen, estradiol, and hematocrit. Most dropouts were related to persistent TD symptoms and serum testosterone <300 ng/dL, with similar rates between the groups in the study. Clinical Implications: Men treated with Testopel and E100 pellets had comparable serum testosterone levels and similar adverse event rates, providing an effective choice of long-term TTh among men with TD. Strengths and Limitations: Strengths include the prospective, randomized, single-blinded study design and adequate follow-up. Limitations include the lack of external validity and the single-institution cohort. Conclusion: E100 compounded testosterone pellets are a noninferior option of TTh as compared with Testopel for men presenting with TD.

The Effect of Sperm DNA Fragmentation on Male Fertility and Strategies for Improvement: A Narrative Review.

The inability to conceive due to male infertility is a complex issue with a wide variety of etiologies. Sperm DNA damage can be both a barrier to natural pregnancy and successful assisted reproductive technology (ART). The aim of this narrative review was to describe and highlight the effects of sperm DNA fragmentation and the most recent data on various treatment strategies to decrease sperm DNA damage. Finally, we proposed a management algorithm for couples undergoing ART with increased sperm DNA fragmentation.

SARS-CoV-2 in the Prostate: Immunohistochemical and Ultrastructural Studies.

The novel coronavirus SARS-CoV-2 was discovered in 2019 and has proven to be a significant public health challenge. While viruses from the coronavirus family have been established as causes of respiratory tract infections, SARS-CoV-2 has also been found in the heart, kidney, testes, and penis. This paper investigates whether SARS-CoV-2 can linger in the prostate by examining the histopathological, ultrastructural, and immunofluorescent elements of prostatic tissue from a patient who was infected by the SARS-CoV-2 virus prior to having a holmium laser enucleation of the prostate (HoLEP) procedure. The findings of this case report suggest that COVID-19 has both the ability to enter prostatic tissue during an acute infection and persist over a timeframe beyond the initial infection period as RNA-containing viral bodies. This case report lays the foundation for future investigations to examine any histopathological changes to the prostatic tissue that may be associated with SARS-CoV-2 viral infection.

Consumption of a Healthy Plant-based Diet is Associated With a Decreased Risk of Erectile Dysfunction: A Cross-sectional Study of the National Health and Nutrition Examination Survey.

OBJECTIVE: To investigate the association between the plant-based content of diet and erectile dysfunction in men from the National Health and Nutrition Examination Survey (NHANES). METHODS: We collected de-identified information from the NHANES database on demographics, comorbidities, diet, and erectile dysfunction (ED). Exclusion criteria were age <20 or >70 years, incomplete plant-based diet index information, history of prostate cancer, or other missing information. Using the food frequency questionnaire, an overall plant-based diet index (PDI) and healthful plant-based diet index (hPDI) were developed. A higher score on the PDI and hPDI is indicative of greater consumption of plant-based foods. RESULTS: A total of 2549 men were analyzed, of those 1085 (42.6%) have good erectile function and 1464 (57.4%) have some degree of ED [usually have erections 521 (20.4%), sometimes have erection 690 (27.1%), or never have erections 253 (9.9%)]. The median age and BMI were 54 [41-64] years and 28.8 [25.5-32.6] kg/m2, respectively. The median PDI and hPDI were 50 [46-54] and 50 [45-56], respectively. In multivariable adjusted logistic regression analysis, hPDI was negatively associated with ED (OR = 0.98, 95% CI: 0.96-0.99; P = .001). There was no association between PDI and ED. CONCLUSION: In a well characterized national database, we showed that a healthful plant-based diet is associated with less chance of having erectile dysfunction. Whether interventions with a plant-based diet will improve erectile function remains to be studied.

Testosterone therapy in children and adolescents: to whom, how, when?

Male production of testosterone is crucial for the development of a wide range of functions. External and internal genitalia formation, secondary sexual characteristics, spermatogenesis, growth velocity, bone mass density, psychosocial maturation, and metabolic and cardiovascular profiles are closely dependent on testosterone exposure. Disorders in androgen production can present during all life-stages, including childhood and adolescence, and testosterone therapy (TT) is in many cases the only treatment that can correct the underlying deficit. TT is controversial in the pediatric population as hypoandrogenism is difficult to classify and diagnose in these age groups, and standardized protocols of treatment and monitorization are still lacking. In pediatric patients, hypogonadism can be central, primary, or a combination of both. Testosterone preparations are typically designed for adults' TT, and providers need to be aware of the advantages and disadvantages of these formulations, especially cognizant of supratherapeutic dosing. Monitoring of testosterone levels in boys on TT should be tailored to the individual patient and based on the anticipated duration of therapy. Although clinical consensus is lacking, an approximation of the current challenges and common practices in pediatric hypoandrogenism could help elucidate the broad spectrum of pathologies that lie behind this single hormone deficiency with wide-ranging implications.

Whole Exome Sequencing Identifies a Rare Mutation in NACAD as a Possible Cause of COVID Orchitis in Brothers.

COVID orchitis (testicular pain) is reported in 10-15% of men with long COVID. We identified 2 siblings with COVID orchitis and hypothesized that genetic mutations are associated with susceptibility. Blood samples from 5 COVID-19 (+) men, three of whom had orchitis were evaluated by whole-exome-sequencing. A rare deletion on chromosome 7 was found in NACAD among the 3 men with orchitis. Interestingly, circulating ACE2 levels was decreased in men with COVID orchitis. This pilot study generated the hypothesis that men who develop COVID orchitis could have underlying genetic variants and altered levels in circulating ACE2 that may increase their risk.

Algorithms for Predicting the Probability of Azoospermia from Follicle Stimulating Hormone: Design and Multi-Institutional External Validation.

PURPOSE: To predict the probability of azoospermia without a semen analysis in men presenting with infertility by developing an azoospermia prediction model. MATERIALS AND METHODS: Two predictive algorithms were generated, one with follicle stimulating hormone (FSH) as the only input and another logistic regression (LR) model with additional clinical inputs of age, luteinizing hormone, total testosterone, and bilateral testis volume. Men presenting between 01/2016 and 03/2020 with semen analyses, testicular ochiodemetry, and serum gonadotropin measurements collected within 120 days were included. An azoospermia prediction model was developed with multi-institutional two-fold external validation from tertiary urologic infertility clinics in Chicago, Miami, and Milan. RESULTS: Total 3,497 participants were included (n=Miami 946, Milan 1,955, Chicago 596). Incidence of azoospermia in Miami, Milan, and Chicago was 13.8%, 23.8%, and 32.0%, respectively. Predictive algorithms were generated with Miami data. On Milan external validation, the LR and quadratic FSH models both demonstrated good discrimination with areas under the receiver-operating-characteristic (ROC) curve (AUC) of 0.79 and 0.78, respectively. Data from Chicago performed with AUCs of 0.71 for the FSH only model and 0.72 for LR. Correlation between the quadratic FSH model and LR model was 0.95 with Milan and 0.92 with Chicago data. CONCLUSIONS: We present and validate algorithms to predict the probability of azoospermia. The ability to predict the probability of azoospermia without a semen analysis is useful when there are logistical hurdles in obtaining a semen analysis or for reevaluation prior to surgical sperm extraction.

Novel methods to enhance surgical sperm retrieval: a systematic review.

Objectives: To explore the use of novel technologies in sperm retrieval in men with azoospermia due to a production defect. Methods: We performed a Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA)-compliant systemic literature review for manuscripts focussed on novel sperm-retrieval methods. We identified 30 studies suitable for qualitative analysis. Results and Conclusions: We identified multiple new promising technologies, each with its own distinct set of benefits and limitations, to enhance chances of sperm retrieval; these include the use of multiphoton microscopy, Raman spectroscopy, and full-field optical coherence tomography during a microdissection-testicular sperm extraction procedure. ORBEYE and ultrasonography technologies can also serve to better visualise areas of sperm production. Finally, artificial intelligence technology can play a role in the identification of sperm and, perhaps, better-quality sperm for use with assisted reproduction. Abbreviations: AI: artificial intelligence; ANN: artificial neural network; ART: assisted reproductive technology; 3D: three-dimensional; DNN: deep neural networks; FFOCT: full-field optical coherence tomography; H&E: haematoxylin and eosin; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilisation; MESA: micro-epididymal sperm aspiration; MeSH: Medical Subject Heading; MPM: multiphoton microscopy; (N)OA: (non-)obstructive azoospermia; SCO: Sertoli cell-only syndrome; SRR: sperm retrieval rates; TESA: testicular sperm aspiration; (micro-)TESE: (microdissection-) testicular sperm extraction; (CE)US: (contrast-enhanced) ultrasonography.

An update on the available and emerging pharmacotherapy for adults with testosterone deficiency available in the USA.

Introduction: Testosterone deficiency (TD) is defined as low serum testosterone associated with symptoms and signs. There has been an increasing prevalence of TD in recent decades, especially in males aged 15-39. Many of these men will require long-term testosterone therapy (TT). Although the end-goals for all treatments are essentially the same, strategies for increasing serum testosterone should be decided individually.Areas covered: This review focuses on the pharmacological management of TD in adults which includes TT with different routes of administration, such as transdermal, buccal, intramuscular and subcutaneous injections, pellets, nasal gel, and oral (pills). The authors review the options for TT available in the USA with emphasis on newer therapies. Furthermore, they examine the efficacy of these therapies with comparison between potential advantages or disadvantages related to dosing, administration method, and adverse events.Expert opinion: Treating TD can be difficult due to the wide range of available medications, diverse side effects related to testosterone replacement and route-of-administration, and necessity for long-term therapy. The combination of pharmacological and non-pharmacological therapies can improve symptoms of TD and patient satisfaction. Each patient should be managed individually, and clinicians should consider available treatment regimens based on the route-of-administration, efficacy, safety, and cost based on a shared decision-making approach.

COVID-19 Endothelial Dysfunction Can Cause Erectile Dysfunction: Histopathological, Immunohistochemical, and Ultrastructural Study of the Human Penis.

PURPOSE: A pilot study to describe histopathological features of penile tissue of patients who recovered from symptomatic COVID-19 infection and subsequently developed severe erectile dysfunction (ED). MATERIALS AND METHODS: Penile tissue was collected from patients undergoing surgery for penile prosthesis for severe ED. Specimens were obtained from two men with a history of COVID-19 infection and two men with no history of infection. Specimens were imaged with TEM and H&E staining. RT-PCR was performed from corpus cavernosum biopsies. The tissues collected were analyzed for endothelial Nitric Oxide Synthase (eNOS, a marker of endothelial function) and COVID-19 spike-protein expression. Endothelial progenitor cell (EPC) function was assessed from blood samples collected from COVID-19 (+) and COVID-19 (-) men. RESULTS: TEM showed extracellular viral particles ~100 nm in diameter with peplomers (spikes) near penile vascular endothelial cells of the COVID-19 (+) patients and absence of viral particles in controls. PCR showed presence of viral RNA in COVID-19 (+) specimens. eNOS expression in the corpus cavernosum of COVID-19 (+) men was decreased compared to COVID-19 (-) men. Mean EPC levels from the COVID-19 (+) patients were substantially lower compared to mean EPCs from men with severe ED and no history of COVID-19. CONCLUSIONS: Our study is the first to demonstrate the presence of the COVID-19 virus in the penis long after the initial infection in humans. Our results also suggest that widespread endothelial cell dysfunction from COVID-19 infection can contribute to ED. Future studies will evaluate novel molecular mechanisms of how COVID-19 infection leads to ED.