How to Achieve High-Quality Oocytes? The Key Role of Myo-Inositol and Melatonin

Assisted reproductive technologies (ART) have experienced growing interest from infertile patients seeking to become pregnant. The quality of oocytes plays a pivotal role in determining ART outcomes. Although many authors have studied how supplementation therapy may affect this important parameter for both in vivo and in vitro models, data are not yet robust enough to support firm conclusions. Regarding this last point, in this review our objective has been to evaluate the state of the art regarding supplementation with melatonin and myo-inositol in order to improve oocyte quality during ART. On the one hand, the antioxidant effect of melatonin is well known as being useful during ovulation and oocyte incubation, two occasions with a high level of oxidative stress. On the other hand, myo-inositol is important in cellular structure and in cellular signaling pathways. Our analysis suggests that the use of these two molecules may significantly improve the quality of oocytes and the quality of embryos: melatonin seems to raise the fertilization rate, and myo-inositol improves the pregnancy rate, although all published studies do not fully agree with these conclusions. However, previous studies have demonstrated that cotreatment improves these results compared with melatonin alone or myo-inositol alone. We recommend that further studies be performed in order to confirm these positive outcomes in routine ART treatment

Diabete mellito: "una nuova causa di infertilità"

Introduzione: Il diabete mellito (DM) può determinare infertilità maschile agendo a livello pre-testicolare, testicolare e post-testicolare. Scopo della tesi: valutare la presenza di infertilità maschile e i meccanismi di danno spermatico nei pazienti con DM in età fertile. Materiali e Metodi: Sono stati arruolati 34 pazienti con DM1, 55 pazienti con DM2, e 100 soggetti fertili sani controllo normale . I pazienti diabetici sono stati ulteriormente suddivisi in 3 gruppi sulla base del compenso glicometabolico e della durata di malattia. Sono stati eseguiti: esame standard del liquido seminale e valutazione citofluorimetrica dei parametri spermatici non convenzionali (frammentazione del DNA nemaspermico, valutazione del grado di vitalità, apoptosi precoce e apoptosi tardiva e del grado di condensazione cromatinica; studio del potenziale di membrana mitocondriale, MMP), formula leucocitaria nell eiaculato mediante analisi citofluorimetrica, valutazione del grado di perossidazione lipidica (PL), e dei livelli spermatici di superossido mitocondriale, ecografia didimo-epididimaria e determinazione sierica in chemiluminescenza di testosterone totale, LH. Risultati: i pazienti diabetici presentano concentrazione nemaspermica, motilità progressiva e morfologia ridotte rispetto al gruppo di controllo (p<0.05). Il volume dell eiaculato è significativamente inferiore nei pazienti con DM1 (p<0.05), ma sembra non subire variazioni significative nei pazienti con DM2 rispetto al gruppo di controllo. Le concentrazioni di leucociti risultano più elevate solo nei pazienti con DM2 (p<0.05), registrando una riduzione statisticamente significativa della percentuale di linfociti T helper nel liquido seminale e un aumento di quella dei linfociti T suppressor rispetto ai soggetti di controllo (p<0.05) L analisi dei parametri spermatici non convenzionali ha mostrato un peggioramento dell MMP nei pazienti diabetici (p<0.05). Solo i pazienti con DM2 hanno mostrato una riduzione significativa del grado di vitalità nemaspermica con aumento di apoptosi tardiva rispetto al gruppo di controllo e della frammentazione del DNA rispetto agli altri due gruppi (p<0.05). Quando suddivisi per durata di malattia, i pazienti con DM1 presentano una motilità progressiva minore nei casi di lunga (>10 anni) durata di malattia rispetto agli altri due gruppi, accompagnata da basso MMP dopo 5 anni di malattia (p<0.05). Il grado di PL è maggiore nel gruppo con DM2 rispetto agli altri due gruppi (p<0.05), mentre le concentrazioni di superossido mitocondriale risultano maggiori nei diabetici rispetto al gruppo di controllo, e maggiori nel DM2 maggiori rispetto al DM1 (p<0.05). I dati ecografici mostrano che il diametro del caput e della coda dell epididimo dopo eiaculazione sono maggiori rispetto al controllo nei pazienti con DM1 di lunga durata rispetto a quelli di breve durata (p<0.05). I livelli di TT risultano più bassi nei DM2 rispetto al gruppo di controllo (p<0.05). Conclusione: i pazienti con DM1 presentano bassi volumi dell eiaculato per mancato svuotamento epididimario, associato ad un danno mitocondriale che anticipa il successivo declino della motilità nemaspermica. A questi dati si associa comunque, un aumento dello stress ossidativo in grado di alterare anche gli altri parametri convenzionali del liquido seminale, anche se in misura minore rispetto al DM2. Il DM2 si caratterizza invece per una condizione infiammatoria con incremento leucocitaria, anche in assenza di infezione causata da specifico agente microbico, in grado di innalzare gli indici di stress ossidativo determinando un danno non solo dei parametri convenzionali del liquido seminale ma anche a carico del DNA spermatico riducendone inoltre anche la vitalità

Globozoospermia: A Case Report and Systematic Review of Literature

Purpose: Globozoospermia is a genetic syndrome characterized by the presence of round-headed spermatozoa and infertility due to the inability of these spermatozoa to fertilize the oocyte. In this article, we present the clinical case of a young globozoospermic patient with a new, not yet described mutation of the DPY19L2 gene. We also performed a systematic review of the literature on gene mutations, the outcome of assisted reproductive techniques, and the risk of transmission of abnormalities to the offspring in patients with globozoospermia and made recommendations to offer a more appropriate clinical management of these patients. Materials and Methods: We performed a systematic search in the PubMed, Google Scholar, and Scopus databases from their inception to December 2021. The search strategy included the combination of the following Medical Subjects Headings (MeSH) terms and keywords: “globozoospermia”, “round-headed spermatozoa”, “round head spermatozoa”, “intracytoplasmic sperm injection”, “ICSI”, “offspring”, “child health”, “assisted reproductive technique outcome”. All the eligible studies were selected following the PECOS (Population, Exposure, Comparison/Comparator, Outcomes, Study design) model. The quality of included studies was assessed by applying the “Cambridge Quality Checklists”. Results: The main genes involved in the pathogenesis of globozoospermia are DPY19L2, SPATA16, PICK1, GGN, SPACA1, ZPBP, CCDC62, and CCNB3 genes. Other genes could also play a role. These include C2CD6, C7orf61, CCIN, DNH17, DNH6, PIWIL4, and CHPT1. Globozoospermic patients should undergo ART to achieve fertility. In particular, intracytoplasmic sperm injection with assisted oocyte activation or intracytoplasmic morphologically-selected sperm injection appears to be associated with a higher success rate. Patients with globozoospermia should also be evaluated for the high rate of sperm aneuploidy which appears to influence the success rate of ART but does not appear to be associated with an increased risk of transmission of genetic abnormalities to offspring. Conclusions: This systematic review summarizes the evidence on the gene panel to be evaluated, ICSI outcomes, and the\ud health of the offspring in patients with globozoospermia. Evidence-based recommendations on the management of patients with globozoospermia are provided

Substance Abuse and Male Hypogonadism

Progressive deterioration of male reproductive function is occurring in Western countries. Environmental factors and unhealthy lifestyles have been implicated in the decline of testosterone levels and sperm production observed in the last fifty years. Among unhealthy lifestyles, substance and drug abuse is a recognized cause of possible alterations of steroidogenesis and spermatogenesis. Alcohol, opioids and anabolic-androgenic steroids are capable to reduce testosterone production in male interfering with testicular and/or hypothalamic-pituitary function. Other substances such as nicotine, cannabis, and amphetamines alter spermatogenesis inducing oxidative stress and subsequent apoptosis in testicular tissue. Substance and drug abuse is a potentially reversible cause of hypogonadism, defined as the failure of the testis to produce physiological concentrations of testosterone and/or a normal number of spermatozoa. The identification of the abuse is important because the withdrawal of substance intake can reverse the clinical syndrome. This review summarizes the most important clinical and experimental evidence on the effect of substance abuse on testosterone and sperm production

Diabetes Mellitus and Infertility: Different Pathophysiological Effects in Type 1 and Type 2 on Sperm Function

Although the prevalence of sub-infertility in diabetic patients in childbearing age is known, the mechanisms by which diabetes mellitus (DM) causes male infertility are not completely explained. This detrimental effect is achieved with a variety of mechanisms that include pre-testicular, testicular, and post-testicular pathogenetic moments and can be different in type 1 diabetes mellitus (DM1) and type 2 diabetes mellitus (DM2) patients because of type of diabetes, duration of disease, and glycemic metabolic compensation. Aim of this study was to evaluate whether diabetic disease can be considered a risk factor for infertility considering the etiopathogenetic differences between DM1 and DM2 on sperm function. We enrolled 38 DM1 patients and 55 DM2 patients with idiopathic infertility history &gt;12 months, and 100 healthy fertile subjects. The following outcomes were evaluated in optical microscopy and flow cytometry: sperm function (by conventional and biofunctional sperm parameters) and signs of urogenital infection/inflammation (by sperm leukocyte concentrations and indices of oxidative stress). Moreover, an andrological evaluation (by didymo-epididymal ultrasound evaluation, serum total testosterone, LH, and FSH measurements) was performed in DM1 and DM2 patients compared to controls. Diabetic patients showed a higher risk of becoming infertile and the pathophysiological mechanisms of damage were different in DM1 and DM2. Conventional sperm parameters of diabetic patients are worse than controls (p &lt; 0.05). The DM2 caused an inflammatory condition with increased oxidative stress resulting in decreased sperm vitality and increased sperm DNA fragmentation. DM1 altered epididymal voiding causing low ejaculate volume and mitochondrial damage resulting in decreased sperm motility. These findings and evidences support the contention that DM could be regarded as cause of male infertility suggesting that the prevention of diabetic disease in DM2 and the follow-up of seminal parameters in DM1 could prevent fertility decline in these categories of patients

Sex-Specific SARS-CoV-2 Mortality: Among Hormone-Modulated ACE2 Expression, Risk of Venous Thromboembolism and Hypovitaminosis D

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease (COVID-19) appears to have a higher mortality rate in presence of comorbidities and in men. The latter suggests the presence of a possible sex-dependent susceptibility. An enzymatic system involved in this different predisposition could be represented by angiotensin converting enzyme 2 (ACE2). ACE2 is activated and down-regulated by the spike protein of the virus and allows the penetration of SARS-CoV-2 into epithelial cells and myocardium. Data on the experimental animal have shown that 17&amp;szlig;-estradiol increases the expression and activity of ACE2 in both adipose tissue and kidney. Spontaneously hypertensive male mice have a higher myocardial ACE2 expression than females and its levels decrease after orchiectomy. In addition to this first aspect, the recent evidence of an increased frequency of venous thromboembolism in patients with COVID-19 (a clinical element associated with a worse prognosis) calls the attention on the safety of treatment with testosterone, in particular in hypogonadal men with greater genetic predisposition. Evidence that sex hormones are able to modulate the expression of ACE2 could help in interpreting epidemiological results and in designing more appropriate intervention strategies. Moreover, the vitamin D deficiency in elderly men may be worthy of further study regarding the epidemiological aspects of this different susceptibility and lethality between sexes

Follicle-Stimulating Hormone Treatment and Male Idiopathic Infertility: Effects on Sperm Parameters and Oxidative Stress Indices according to FSHR c. 2039 A/G and c. -29 G/A Genotypes

Scientific evidence shows that the administration of follicle-stimulating hormone (FSH) to infertile patients with normal serum FSH concentrations improves sperm parameters in oligozoospermic men. The aim of this study was to evaluate the effects of highly purified urofollitropin (hpFSH) on conventional and bio-functional sperm parameters and on oxidative stress indices in patients with idiopathic infertility. We also evaluated the response to hpFSH on these parameters in relationship to FSHR c. 2039 A/G and FSHR c. -29 G/A genotypes. A prospective longitudinal study was conducted on 42 patients with idiopathic male infertility, 23 of whom underwent to FSHR c. 2039 A/G and FSHR c. -29 G/A genotyping. Each patient was asked to collect two semen samples before and after administration of 150 IU hpFSH three times a week for 16 weeks. Patients were divided into responders or non-responders based on whether their total sperm count had at least doubled or was less than double at the end of treatment, respectively. Responders showed a significantly higher semen volume, sperm concentration, spermatids, and leukocytes. Non-responders had a significant decrease of the percentage of spermatozoa in early apoptosis after hpFSH administration. Oxidative stress indexes did not differ significantly after FSH administration in both groups. Conventional and bio-functional sperm parameters did not differ in patients with FSHR c. 2039 GG and AA genotypes, and FSHR c. -29 GG genotype both before and after FSH administration. The FSHR c. 2039 and FSHR -29 G/A genotypes and allelic distribution did not differ between responders and non-responders. FSH showed to be capable of ameliorating sperm parameters in about half patients treated, therefore it may be helpful in patients with idiopathic infertility

Thyroid Hormones and Spermatozoa: In Vitro Effects on Sperm Mitochondria, Viability and DNA Integrity

The aim of this study wasto assess the in vitro effects of levothyroxine (LT4) on conventional and bio-functional sperm parameters and its implications on fertility. Patients with male idiopathic infertility were enrolled and subjected to examination of the seminal fluid and capacitation according to the WHO 2010 criteria and flow cytometric sperm analysis for the evaluation of bio-functional sperm parameters. LT4 significantly increased the percentage of spermatozoa with high mitochondrial membrane potential (MMP), decreased the percentage of spermatozoa with low MMP and increased sperm motility already at a concentration of 0.9 pmol L&#8722;1. Therefore, LT4 significantly reduced sperm necrosis and lipid peroxidation ameliorating chromatin compactness. These effects of LT4 were evident at a concentration of 2.9 pmol L&#8722;1, close to the physiological free-thyroxine (FT4) concentrations in the seminal fluid of euthyroid subjects. We showed a beneficial role of thyroid hormones on sperm mitochondrial function, oxidative stress and DNA integrity. The results of this in vitro study could have a clinical application in patients with idiopathic infertility, clarifying the role of thyroid function on male fertility

Epigenetics of Male Fertility: Effects on Assisted Reproductive Techniques

During the last decades the study of male infertility and the introduction of the assisted reproductive techniques (ARTs) has allowed to understand that normal sperm parameters do not always predict fertilization. Sperm genetic components could play an important role in the early stages of embryonic development. Based on these acquisitions, several epigenetic inves-tigations have been developed on spermatozoa, with the aim of understanding the multifactorial etiology of male infertility and of showing whether embryonic development may be influenced by sperm epigenetic abnormalities. This article reviews the possible epigenetic modifications of spermatozoa and their effects on male fertility, embryonic development and ART outcome. It focuses mainly on sperm DNA methylation, chromatin remodeling, histone modifications and RNAs

Metabolism and Ovarian Function in PCOS Women: A Therapeutic Approach with Inositols

Polycystic ovary syndrome (PCOS) is characterized by chronical anovulation and hyperandrogenism which may be present in a different degree of severity. Insulin-resistance and hyperinsulinemia are the main physiopathological basis of this syndrome and the failure of inositol-mediated signaling may concur to them. Myo (MI) and D-chiro-inositol (DCI), the most studied inositol isoforms, are classified as insulin sensitizers. In form of glycans, DCI-phosphoglycan and MI-phosphoglycan control key enzymes were involved in glucose and lipid metabolism. In form of phosphoinositides, they play an important role as second messengers in several cellular biological functions. Considering the key role played by insulin-resistance and androgen excess in PCOS patients, the insulin-sensitizing effects of both MI and DCI were tested in order to ameliorate symptoms and signs of this syndrome, including the possibility to restore patients’ fertility. Accumulating evidence suggests that both isoforms of inositol are effective in improving ovarian function and metabolism in patients with PCOS, although MI showed the most marked effect on the metabolic profile, whereas DCI reduced hyperandrogenism better. The purpose of this review is to provide an update on inositol signaling and correlate data on biological functions of these multifaceted molecules, in view of a rational use for the therapy in women with PCOS