The Possible Role of Prescribing Medications, Including Central Nervous System Drugs, in Contributing to Male-Factor Infertility (MFI): Assessment of the Food and Drug Administration (FDA) Pharmacovigilance Database

© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY), https://creativecommons.org/licenses/by/4.0/Background: A wide range of medications may have a possible role in the development of male-factor infertility (MFI), including various antineoplastic agents, testosterone/anabolic steroids, immunosuppressive drugs/immunomodulators, glucocorticosteroids, non-steroidal an-ti-inflammatory drugs, opiates, antiandrogenic drugs/5-alpha-reductase inhibitors, various antibi-otics, antidepressants, antipsychotics, antiepileptic agents and others. We aimed at investigating this issue from a pharmacovigilance-based perspective. Methods: The Food and Drug Administra-tion (FDA) Adverse Event Reporting System (FAERS) database was queried to identify the drugs associated the most with MFI individual reports. Only those drugs being associated with more than 10 MFI reports were considered for the disproportionality analysis. Proportional Reporting Ratios (PRRs) and their confidence intervals were computed for all the drugs identified in this way in January 2023. Secondary, ‘unmasking’, dataset analyses were carried out as well. Results: Out of the whole database, 955 MFI reports were identified, 408 (42.7%) of which were associated with 20 medications ,which had more than 10 reports each. Within this group, finasteride, testosterone, valproate, diethylstilbestrol, mechloretamine, verapamil, lovastatin and nifedipine showed signif-icant levels of actual disproportionate reporting. Out of these, and before unmasking, the highest PRR values were identified for finasteride, diethylstilbestrol and mechloretamine, respectively, with values of 16.0 (12.7–20.3), 14.3 (9.1–22.4) and 58.7 (36.3–95.9). Conclusions: A variety of several medications, a number of which were already supposed to be potentially linked with MFI based on the existing evidence, were associated with significant PRR levels for MFI in this analysis. A number of agents which were previously hypothesized to be associated with MFI were not represented in this analysis, suggesting that drug-induced MFI is likely under-reported to regulatory agencies. Reproductive medicine specialists should put more effort into the detection and reporting of these adverse drug reactions.Peer reviewe

Recreational Drug Misuse and Its Potential Contribution to Male Fertility Levels’ Decline: A Narrative Review

© 2022 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)Recreational drug intake may be associated with a range of medical untoward consequences, including male infertility. However, as the related evidence is still limited, the main outcome of this review is to provide a better understanding of the existence of any association between recreational drug misuse and male fertility levels’ decline. Whilst searching the MEDLINE/PubMed, a comprehensive overview of the literature regarding male infertility and substances of abuse (e.g., phytocannabinoids, opiates/opioids, stimulants, ‘herbal highs’, psychedelics, and ‘novel psychoactive substances) was here undertaken. Due to the paucity of robust, high-quality, empirical, human studies, a narrative strategy was here preferred over a systematic approach. Relevant data are qualitatively analyzed and presented in a table. Although most available evidence is in support of a detrimental role of cannabis on human spermatogenesis, a few remaining studies failed to document any effect of this drug on seminal quality, and it is not clear to which extent this drug impacts fertility rates/time to pregnancy. The current understanding of the impact of opiate-, cocaine- and amphetamine/stimulant-misuse on human reproduction is widely unknown, and most studies dealing with this matter represent only an extrapolation of data derived from specific clinical circumstances. Although the message of ‘no smoking, no alcohol and no street drugs’ should always be offered as good health advice to all patients seeking medical help for fertility issues, robust scientific clinical evidence in support of a direct detrimental impact of recreational drugs on spermatogenesis is scant to date.Peer reviewe

COVID-19 disease in clinical setting: impact on gonadal function, transmission risk, and sperm quality in young males.

Abstract Objectives We want to evaluate the possible presence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in semen samples and semen quality, looking for a possible relationship between the infectious disease and fertility. Methods In this prospective study, we enrolled 15 consecutive men (age 18–50 years) with positive oropharyngeal swab to SARS-CoV-2 and classified, according to WHO criteria, in mild to moderate disease. A semen sample was collected to detect SARS-CoV viral RNA by the automated Real-Time PCR ELITe InGenius® system and the GeneFinderTM COVID-19 Plus RealAmp Kit assay (ELITechGroup, France). Analysis of semen characteristics was performed according to WHO laboratory manual 5th ed. for the examination and processing of human semen. Blood samples for the dosage of hormonal assay, procalcitonin, interleukin 6, C-reactive protein were obtained. Results SARS-CoV-2 RNA has not been detected in semen samples from any of the subjects analysed. Sperm analysis exhibited abnormal seminal values in 14 out of 15 patients (93.3%). Furthermore, no difference was detected regarding sperm quality between mild and moderate SARS-CoV-2 patients. No alteration in the inflammatory indices was observed in the studied population, as well gonadotropins and testosterone levels. Conclusions COVID patients studied exhibits alteration of the seminal fluid both in microscopic and macroscopic characteristics such as hypoposia and increased viscosity, which have not been detected in previous studies. The presence of viral RNA within the seminal fluid was excluded

The Application of Hyaluronic Acid Injections in Functional and Aesthetic Andrology: A Narrative Review

Hyaluronic acid (HA) is a glycosaminoglycan widely utilised in different fields of medicine. We aimed to provide a comprehensive overview of the scientific evidence on the use of HA in andrology. A review of the literature to identify pertinent studies concerning the use of HA in andrology was carried out on the Medline, EMBASE, and the Cochrane databases, with no time restriction up to December 2022. Penile girth enlargement (PGE) using HA proved to be safe and effective in enhancing the diameter of the penis, with durable and satisfactory outcomes in long-term follow-up. Injection of HA in the glans seems to represent an alternative treatment option for those patients with premature ejaculation (PE) who fail to respond to conventional medications. HA intra-plaque injections represent a valid option which may contribute to restore sexual activity in patients with Peyronie’s disease (PD). The adoption of HA filler injections should always be tailored to the patient’s peculiar anatomy and underlying condition. More robust evidence is required to achieve a uniformed consensus regarding the use of HA in andrology, and further efforts should continue to improve the current injection techniques and HA products

The tumor innate immune microenvironment in prostate cancer: an overview of soluble factors and cellular effectors

Prostate cancer (PCa) accounts as the most common non-cutaneous disease affecting males, and as the first cancer, for incidence, in male. With the introduction of the concept of immunoscore, PCa has been classified as a cold tumor, thus driving the attention in the development of strategies aimed at blocking the infiltration/activation of immunosuppressive cells, while favoring the infiltration/activation of anti-tumor immune cells. Even if immunotherapy has revolutionized the approaches to cancer therapy, there is still a window failure, due to the immune cell plasticity within PCa, that can acquire pro-tumor features, subsequent to the tumor microenvironment (TME) capability to polarize them. This review discussed selected relevant soluble factors [transforming growth factor-beta (TGFβ), interleukin-6 (IL-6), IL-10, IL-23] and cellular components of the innate immunity, as drivers of tumor progression, immunosuppression, and angiogenesis within the PCa-TME

The Complex Interplay between Serum Testosterone and the Clinical Course of Coronavirus Disease 19 Pandemic: A Systematic Review of Clinical and Preclinical Evidence

Since the beginning of the coronavirus disease 19 (COVID-19) pandemic, efforts in defining risk factors and associations between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), clinical, and molecular features have initiated. After three years of pandemic, it became evident that men have higher risk of adverse outcomes. Such evidence provided the impetus for defining the biological fundaments of such a gender disparity. Our objective was to analyze the most recent literature with the aim of defining the relationship between COVID-19 and fertility, in particular, we assessed the interplay between SARSCoV- 2 and testosterone in a systematic review of literature from December 2019 (first evidence of a novel coronavirus in the Hubei province) until March 2022. As a fundamental basis for understanding, articles pertaining preclinical aspects explaining the gender disparity (n=9) were included. The main review categories analyzed the risk of being infected with SARS-CoV-2 according to testosterone levels (n=5), the impact of serum testosterone on outcomes of COVID-19 (n=23), and the impact SARSCoV- 2 on testosterone levels after infection (n=19). Preclinical studies mainly evaluated the relation between angiotensinconverting enzyme 2 (ACE2) and its androgen-mediated regulation, articles exploring the risk of COVID-19 according to testosterone levels were few. Although most publications evaluating the effect of COVID-19 on fertility found low testosterone levels after the infection, follow-up was short, with some also suggesting no alterations during recovery. More conclusive findings were observed in men with low testosterone levels, that were generally at higher risk of experiencing worse outcomes (i.e., admission to intensive care units, longer hospitalization, and death). Interestingly, an inverse relationship was observed in women, where higher levels of testosterone were associated to worse outcomes. Our finding may provide meaningful insights to better patient counselling and individualization of care pathways in men with testosterone levels suggesting hypogonadism

Recreational drug misuse and its potential contribution to male fertility levels' decline: a narrative review.

Recreational drug intake may be associated with a range of medical untoward consequences, including male infertility. However, as the related evidence is still limited, the main outcome of this review is to provide a better understanding of the existence of any association between recreational drug misuse and male fertility levels' decline. Whilst searching the MEDLINE/PubMed, a comprehensive overview of the literature regarding male infertility and substances of abuse (e.g., phytocannabinoids, opiates/opioids, stimulants, 'herbal highs', psychedelics, and 'novel psychoactive substances) was here undertaken. Due to the paucity of robust, high-quality, empirical, human studies, a narrative strategy was here preferred over a systematic approach. Relevant data are qualitatively analyzed and presented in a table. Although most available evidence is in support of a detrimental role of cannabis on human spermatogenesis, a few remaining studies failed to document any effect of this drug on seminal quality, and it is not clear to which extent this drug impacts fertility rates/time to pregnancy. The current understanding of the impact of opiate-, cocaine- and amphetamine/stimulant-misuse on human reproduction is widely unknown, and most studies dealing with this matter represent only an extrapolation of data derived from specific clinical circumstances. Although the message of 'no smoking, no alcohol and no street drugs' should always be offered as good health advice to all patients seeking medical help for fertility issues, robust scientific clinical evidence in support of a direct detrimental impact of recreational drugs on spermatogenesis is scant to date

A Proposal of a New Nomogram to Predict the Need for Testosterone ReplACEment (TRACE): A Simple Tool for Everyday Clinical Practice

International guidelines suggest to use testosterone therapy (TTh) in hypogonadal men presenting symptoms of testosterone deficiency (TD), even if there is no fixed threshold level of T at which TTh should be started. We aimed to develop and validate a nomogram named TRACE (Testosterone ReplACEment) for predicting the need of TTh in patients with “low–normal” total testosterone levels. The following nomogram variables were used: serum T level; serum LH level; BMI; state of nocturnal erections; metabolic comorbidities; and IPSS total score. The nomogram has been tested by calculating concordance probabilities, as well as assaying the calibration of predicted probability of clinical testosterone deficiency and need for TTh, together with the clinical outcome of the TTh. A cohort of 141 patients was used for the development of the nomogram, while a cohort of 123 patients attending another institution was used to externally validate and calibrate it. Sixty-four patients (45.3%) received TTh. Among them, sixty patients (93.7%) reported a significant clinical improvement after TTh. The nomogram had a concordance index of 0.83 [area under the ROC curve 0.81 (95% CI 0.71–0.83)]. In conclusion, the TRACE nomogram accurately predicted the probability of clinical impairment related to TD, and resulted in a simple and reliable method to use to select hypogonadal patients with not clearly pathological testosterone values who will benefit from TTh