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Cardiovascular disease is the most important cause of death worldwide in recent years; an increasing trend is also shown in organ transplant patients subjected to immunosuppressive therapies, in which cardiovascular diseases represent one of the most frequent causes of long-term mortality. This is also linked to immunosuppressant-induced dyslipidemia, which occurs in 27 to 71% of organ transplant recipients. The aim of this review is to clarify the pathophysiological mechanisms underlying dyslipidemia in patients treated with immunosuppressants to identify immunosuppressive therapies which do not cause dyslipidemia or therapeutic pathways effective in reducing hypercholesterolemia, hypertriglyceridemia, or both, without further adverse events.

We thank our French colleagues for commenting [...].

Background: In the last 40 years, assisted reproductive techniques (ARTs) have emerged as potentially resolving procedures for couple infertility. This study aims to evaluate whether ART is associated with epigenetic dysregulation in the offspring. Methods. To accomplish this, we collected all available data on methylation patterns in offspring conceived after ART and in spontaneously conceived (SC) offspring. Results. We extracted 949 records. Of these, 50 were considered eligible; 12 were included in the quantitative synthesis. Methylation levels of H19 CCCTC-binding factor 3 (CTCF3) were significantly lower in the ART group compared to controls (SMD −0.81 (−1.53; −0.09), I2 = 89%, p = 0.03). In contrast, H19 CCCTC-binding factor 6 (CTCF6), Potassium Voltage-Gated Channel Subfamily Q Member 1 (KCNQ1OT1), Paternally-expressed gene 3 (PEG3), and Small Nuclear Ribonucleoprotein Polypeptide N (SNRPN) were not differently methylated in ART vs. SC offspring. Conclusion: The methylation pattern of the offspring conceived after ART may be different compared to spontaneous conception. Due to the lack of studies and the heterogeneity of the data, further prospective and well-sized population studies are needed to evaluate the impact of ART on the epigenome of the offspring.

Lymph node neck metastases are frequent in papillary thyroid carcinoma (PTC). Current guidelines state, on a weak level of evidence, that level VI dissection is mandatory in the presence of latero-cervical metastases. The aim of our study is to evaluate predictive factors for the absence of level VI involvement despite the presence of metastases to the lateral cervical stations in PTC. Eighty-eight patients operated for PTC with level II–V metastases were retrospectively enrolled in the study. Demographics, thyroid function, autoimmunity, nodule size and site, cancer variant, multifocality, Bethesda and EU-TIRADS, number of central and lateral lymph nodes removed, number of positive lymph nodes and outcome were recorded. At univariate analysis, PTC location and number of positive lateral lymph nodes were risk criteria for failure to cure. ROC curves demonstrated the association of the number of positive lateral lymph nodes and failure to cure. On multivariate analysis, the protective factors were PTC located in lobe center and number of positive lateral lymph nodes &lt, 4. Kaplan–Meier curves confirmed the absence of central lymph nodes as a positive prognostic factor. In the selected cases, Central Neck Dissection (CND) could be avoided even in the presence of positive Lateralcervical Lymph Nodes (LLN+).

A physical examination represents a fundamental step in diagnosing diseases. Due to the role that hormones play in the regulation of numerous biological processes in various organs and systems, endocrine diseases cause a variety of clinical manifestations that can be easily identified with a careful physical examination and can guide the clinician to specific diagnoses. Furthermore, the presence of specific clinical signs in various endocrine-metabolic diseases can predict the risk of developing comorbidities and serious adverse events. In this article, we present some of the main clinical signs of endocrine-metabolic diseases and the risk of comorbidities, summarizing the pathogenetic mechanisms that lead to their formation. The aim is to highlight how the identification of these specific signs can reduce the number of dynamic tests and the costs necessary to reach the diagnosis and allow the early identification of any complications associated with these diseases, improving the clinical management of affected patients.

Purpose: To prospectively investigate the effects of treatment with liraglutide, a glucagon-like peptide 1 (GLP1) analog, on reproductive and sexual function in men with metabolic hypogonadism who are of childbearing age. Materials and Methods: To accomplish this purpose, 110 men of childbearing age (18–35 years) with metabolic hypogonadism were enrolled and divided into three groups, according to their desire to have children. Group A was made up of men actively seeking fatherhood, Group B, of men who did not seek fatherhood, and Group C, of men who had already fathered a child. Group A patients were treated with gonadotropins (urofollitropin at 150 IU, three times a week, and human chorionic gonadotropin at 2000 IU, twice a week), Group B patients with liraglutide (3 mg daily), and Group C patients with transdermal testosterone (60 mg per day). All patients were treated for 4 months. Results: Patients treated with liraglutide (Group B) showed significant improvement in conventional sperm parameters, compared to baseline and Group A patients, and in the quality of erectile function compared to baseline and patients of Groups A and C. In addition, they had significantly higher levels of total testosterone and sex hormone-binding globulin serum levels after 4 months of treatment with liraglutide than those achieved by patients in the other two groups at the end of the respective treatments. Finally, Group B patients also showed significantly higher serum gonadotropin levels than the other groups. Conclusions: The results of this study showed, for the first time, the efficacy of liraglutide, a GLP1 analog, for the pharmacological treatment of male patients with metabolic hypogonadism. Liraglutide has also shown advantages over traditional treatments on both reproductive and sexual function and appears to offer greater benefits in terms of metabolic protection. These findings suggest that liraglutide is a useful drug for the treatment of obese males with metabolic hypogonadism.

The protocols commonly used in assisted reproductive technology (ART) consist of long-term embryo culture up to the blastocyst stage after the insemination of all mature oocytes, the freezing of all the embryos produced, and their subsequent transfer one by one. These practices, along with preimplantation genetic testing, although developed to improve the live birth rate (LBR) and reduce the risk of multiple pregnancies, are drawing attention to the possible increase in obstetric and perinatal risks, and adverse epigenetic consequences in offspring. Furthermore, ethical–legal concerns are growing regarding the increase in cryopreservation and storage of frozen embryos. In an attempt to reduce the risk associated with prolonged embryo culture and avoid embryo storage, we have chosen to inseminate a limited number of oocytes not exceeding the number of embryos to be transferred, after two days or less of culture. We retrospectively analyzed 245 ICSI cycles performed in 184 infertile couples with a female partner aged ≥40 from January 2016 to July 2021. The results showed a fertilization rate of 95.7%, a miscarriage rate of 48.9%, and a LBR of 10% with twin pregnancies of 16.7%. The cumulative LBR in our group of couples was 13%. No embryos were frozen. In conclusion, these results suggest that oocyte selection and embryo transfer at the cleaving stage constitute a practice that has a LBR comparable to that of the more commonly used protocols in older women who have reduced ovarian reserve.

Background: The management of Philadelphia Chromosome-positive (Ph+) hematological malignancies is strictly correlated to the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, these drugs do not induce leukemic stem cells death and their persistence may generate a disease relapse. Published reports indicated that Venetoclax, a selective BCL2 inhibitor, could be effective in Ph+ diseases, as BCL2 anti-apoptotic activity is modulated by BCR-ABL1 kinase. We, therefore, investigated if BCL2 inhibition, alone or combined with Nilotinib, a BCR-ABL1 inhibitor, affects the primitive and committed Ph+ cells survival. Methods: We used Ph+ cells isolated from leukemic patients at diagnosis. To estimate the therapeutic efficacy of BCL2 and BCR-ABL1 inhibition we employed long-term culture, proliferation and apoptosis assay. Immunoblot was used to evaluate the ability of treatment to interfere with the down-stream targets of BCR-ABL1. Results: Blocking BCL2, we observed reduced proliferation and clonogenic potential of CML CD34-positive cells and this cytotoxicity was improved by combination with BCR-ABL1 inhibitor. However, BCL2 inhibition, alone or in combination regiment with BCR-ABL1 inhibitor, did not reduce the self-renewal of primitive leukemic cells, while strongly induced cell death on primary Ph+ Acute Lymphoblastic Leukemia (ALL). Conclusion: Our results suggest that primitive CML leukemic cells are not dependent on BCL2 for their persistence and support that committed CML and Ph + ALL cells are dependent by BCL2 and BCR-ABL1 cooperation for their survival. The antileukemic activity of BCL2 and BCR-ABL1 dual targeting may be a useful therapeutic strategy for Ph+ ALL patients.

Background: Selenium (Se) is an essential component of selenoenzymes, which have catalytic and antioxidant functions. A low Se status has been reported in patients with chronic autoimmune thyroiditis (AT) who benefit from Se supplementation. The role of Se in male reproduction is still a matter of debate. Although Se and selenoenzymes ensure sperm viability and protect against increased oxidative stress, only a few studies have assessed the effects of the administration of Se alone on sperm parameters, providing contrasting results. Aim: The aim of this study was to assess the effects of oral Se supplementation on conventional sperm parameters and DNA fragmentation (SDF) in patients with AT of reproductive age with normal thyroid function. Patients and Methods: Only patients with AT and normal thyroid function were selected for this study. All included patients underwent oral Se supplementation at the dose of 83 µg once daily (Syrel®, IBSA) for six months. Sperm conventional parameters, SDF, and thyroid function were assessed before and at the end of the treatment. Results: Twenty AT patients with normal weight were enrolled. After Se supplementation, they showed a higher sperm concentration, a higher percentage of sperm with progressive motility, and a higher percentage with normal morphology. They also had lower semen leukocyte concentration, and a lower percentage of spermatozoa with DNA fragmentation compared with pre-treatment values. Free-thyroxine serum levels increased significantly, whereas free triiodothyronine showed an upward trend. The thyroid-stimulating hormone did not change significantly. Conclusion: Se supplementation may represent a possible non-hormonal therapeutic choice for the treatment of male infertility, although further studies are needed to confirm this evidence. The possible thyroid hormone dependency of these findings needs to be clarified.

Follicle-stimulating hormone (FSH) is a therapeutic option in patients with idiopathic oligozoospermia and normal FSH serum levels. However, few studies have evaluated which dose of FSH is more effective. The aim of this study was to compare the clinical efficacy of the two most frequently used FSH treatment regimens: 75 IU daily vs. 150 IU three times a week. Patients were retrospectively assigned to two groups. The first group (n = 24) was prescribed highly purified FSH (hpFSH) 75 IU/daily (Group A), and the second group (n = 24) was prescribed hpFSH 150 IU three times a week (Group B) for three months. Before and after treatment, each patient underwent semen analysis, evaluation of the percentage of DNA-fragmented spermatozoa, assessment of testicular volume (by ultrasonography), and measurement of FSH and total testosterone (TT) serum levels. Treatment with hpFSH significantly improved conventional sperm parameters. In detail, sperm concentration increased significantly after treatment only in Group A, whereas total sperm count, percentage of spermatozoa with progressive motility, normal morphology, or alive improved significantly in both groups. Interestingly, the percentage of sperm DNA fragmentation decreased significantly in both groups after treatment with hpFSH. FSH serum levels were expectably higher at the end of the treatment than before hpFSH was administered to both groups. Remarkably, TT serum levels only increased significantly in Group A. Finally, testicular volume was significantly higher in Group A after treatment, while it did not change significantly compared to baseline in Group B. The percentage of FSH responders did not differ significantly between the two groups (8/24 vs. 6/24). The daily administration of hpFSH 75 IU seems more effective than using 150 IU three times a week. However, this therapeutic scheme implies a higher number of injections and slightly higher costs.

Objective: To evaluate the changes of conventional sperm parameters in men who referred to an andrology reference center in Catania (Eastern Sicily, Italy) in the decade 2011–2020. Methods: For this purpose, we selected–retrospectively and randomly–the reports of 1409 semen analyses performed according to the 2010 WHO criteria. Data on sperm concentration, total sperm count, progressive sperm motility, and percentage of normal forms were analyzed using linear regression of the raw and logarithmic-transformed data. The sperm parameters were subsequently pooled in two five-year periods (2011–2015 and 2016–2020) and compared with each other. Finally, the influence of the city of residence was assessed on five-year pooled data. Main results: A slight but non-significant decline of total sperm count (−2.26 million/year, p = 0.065) and the percentage of spermatozoa with normal morphology (−0.08%/year, p = 0.057) was observed. In contrast, a significant increase of progressive sperm motility (+0.28%/year, p = 0.008) over time was found. The total sperm count of the quinquennium 2016–2020 was significantly lower. and an upward trend of progressive sperm motility was found. compared to the years 2011–2015. No changes in sperm concentration and morphology occurred in the years 2011–2015 vs. 2016–2020. Sperm conventional parameters did not differ when the five-year pooled data were analyzed according to the town of residence. Conclusions: Divergent trends of total sperm count and progressive sperm motility over time were found in patients from Eastern Sicily. This may point out the need of assessing whether a time-dependent change of biofunctional sperm parameters occurs to really understand the trend of sperm quality over time.

Cardiovascular diseases are the main cause of mortality in the Western population, so the attempt to find a marker capable of predicting their early onset is not surprising. It is known that arteriogenic erectile dysfunction (ED) precedes the onset of a major coronary event by several years. However, a marker that is able to early identify those patients who should undergo further diagnostic investigations is, to date, missing. Recent research on this topic has focused on the role of the mean platelet volume (MPV), a marker of platelet activity that is high in most vascular diseases, such as coronary artery disease (CAD), stroke, peripheral artery disease (PAD), and ED. The basic pathophysiological mechanism of all these clinical conditions is atherosclerosis. Platelets play a central role in amplifying this process both indirectly by stimulating endothelial cells to produce inflammatory cytokines and chemokines, and directly through the expression of membrane receptors and the release of molecules that contribute to the formation of atherosclerotic plaque. The objective of this review is to critically analyze the evidence on the role of MPV in predicting the diagnosis and severity of vasculogenic ED and the possibility of using this simple marker as a first step to start a diagnostic process aimed at assessing the cardiovascular risk in these patients.

There is increasing data in favour of follicle-stimulating hormone (FSH) therapy in patients with oligo-asthenozoospermia and normal-range gonadotropins in order to increase sperm count and above all sperm motility. Some studies showed an improvement in DNA fragmentation and spontaneous pregnancy. Recently, biosimilar FSH has been marketed with the same indications. We performed a retrospective multicentric case-control study involving 147 asthenozoospermic patients between 18 and 45 years of age. A total of 97 patients were treated with biosimilar FSH 150 UI three times a week for 3 months, while 50 control subjects received no treatment. Patients were evaluated at baseline and after 3 months with semen analysis including DNA fragmentation, testicular colour Doppler ultrasound, and blood tests. Spontaneous pregnancies were recorded during a further follow-up period of 6 months. Treated patients showed after treatment a statistically significant increase in sperm concentration, total sperm count, and total motile sperm, as well as improved progressive motility and non-progressive motility. DNA fragmentation showed a significant reduction. Conversely, in the control group, no significant change was found. Pregnancy rate was significantly higher in treated patients. These data suggest comparable efficacy of biosimilar FSH in the treatment of male infertility, however, larger studies are needed to confirm our results.

The use of inositols in endocrinological clinical practice is increasingly widespread. Most of the existing evidence concerns myoinositol (MYO), the most abundant form in nature, especially in women with polycystic ovarian syndrome. We have previously shown that MYO increases sperm motility in patients with asthenozoospermia by the increase of sperm mitochondrial membrane potential (MMP), a biofunctional sperm parameter closely associated to sperm motility. The aim of this study was to evaluate the effects of D-chiro-inositol (DCI), another biologically active isoform of inositols, on sperm MMP, as data on this matter has never been released so far. To accomplish this, semen samples from 15 patients with asthenozoospermia and 15 healthy normozoospermic men were incubated with increasing concentrations of DCI (0, 75, and 750 µg/mL) or phosphate buffer saline for 30 min. Incubation with DCI significantly improved sperm MMP at lower concentrations, and with shorter incubation length than those used in our similar MYO studies. In conclusion, these findings indicate that DCI positively impacts on sperm mitochondrial function in vitro. Studies aimed at assessing the role of DCI in the treatment of asthenozoospermia in-vivo are warranted.

Background: Recent studies have supported the beneficial effects of a short abstinence period on sperm parameters. The aim of this study was to assess sperm motility, morphology and DNA fragmentation before and after swim-up of a second ejaculate obtained after a short abstinence period in normozoospermic men and oligo-astheno-teratozoospermic (OAT) patients. Material and methods: Semen analyses and swim-up preparations of two consecutive semen samples (collected within 1 h) were carried out in 30 normozoospermic and 35 OAT patients enrolled in an assisted reproductive technique (ART) program. Results: Compared to the first ejaculate, the second sample showed a higher percentage of spermatozoa with normal form (p &lt, 0.01) and lower percentage of spermatozoa with DNA fragmentation (p &lt, 0.01) in normozoospermic men, whereas a higher percentage of spermatozoa with progressive motility (p &lt, 0.001) and normal morphology (p &lt, 0.0001) was found in OAT patients. Swim-up separation showed a lower DNA fragmentation rate (p &lt, 0.05) in the second ejaculate in normozoospermic men, whereas the second ejaculate of OAT patents showed an increase in normally-shaped spermatozoa (p &lt, 0.01) and lower percentage of spermatozoa with fragmented DNA (p &lt, 0.001) compared to the first one. Conclusions: Swim-up separation of a second ejaculate collected within 1 h might be suggested for ART procedures, especially in OAT patients.

Male infertility is a widespread condition among western countries. Meta-regression data show that sperm concentration and total sperm count have halved in the last decades. The reasons of this decline are still unclear. The evaluation of testicular function in pre-pubertal children may be effective in the timely detection of Sertoli cell (SC) disfunction, which anticipates the diagnosis of male infertility. The aim of this Special Issue is to gather together in vitro evidence on SC physiology, causes of SC dysfunction, and to suggest a practical approach to be adopted in children.

Background: Arterial erectile dysfunction (ED) is an early sign of vascular damage. Rare evidence has been published so far as to whether subclinical hypothyroidism (SCH) affects arterial erectile function. Therefore, the objective of this study was to fill this gap. Methods: Patients with arterial ED and SCH were consecutive enrolled and randomly divided into Group A (n = 20) and Group B (n = 20). Group A was treated with levo-thyroxine (LT4) at the dose of 1 &micro, g/kg/day for six months, whereas patients of the group B did not receive any treatment. Thyroid stimulating hormone (TSH), free-thyroxine (FT4), peak systolic velocity (PSV), International Index of Erectile Function 5-item version (IIEF-5) score, mean platelet volume (MPV), and total cholesterol were evaluated at enrollment (T0) and after six months (T1). Patients without hypertension, diabetes mellitus, dyslipidemia, not on drugs, and with normal total testosterone (TT) values were included in this study. Results: Group A and B did not differ for age (61.2 &plusmn, 4.8 vs. 60.3 &plusmn, 5.6 years), body-mass index (28.7 &plusmn, 2.5 vs. 28.3 &plusmn, 2.6 Kg/m2), and serum TT levels (481.2 &plusmn, 54.0 vs. 492.1 &plusmn, 59.7 ng/dL). At T0, serum TSH levels (6.5 &plusmn, 1.2 vs. 6.0 &plusmn, 1.0 &micro, IU/mL), FT4 (8.8 &plusmn, 0.6 vs. 8.8 &plusmn, 0.6 pmol/L), PSV (26.5 &plusmn, 1.4 vs. 25.8 &plusmn, 2.1 cm/s), IIEF-5 score (8.2 &plusmn, 1.7 vs. 9.0&plusmn, 1.7), and total cholesterol (167.8 &plusmn, 21.7 vs. 171.6 &plusmn, 21.3 mg/dL) did not significantly differ in patients of Group A vs. those of Group B. MPV was significantly higher in Group A than in Group B (12.3 &plusmn, 0.3 vs. 11.8&plusmn, 0.7 fL). At T1, Group A showed significantly lower TSH (2.26 &plusmn, 0.5 &micro, IU/mL), MPV (9.5 &plusmn, 0.3 fL), and total cholesterol (137.8 &plusmn, 29.2 mg/dL) and significantly higher FT4 (9.3 &plusmn, 0.4 pmol/L), PSV (40.0 &plusmn, 2.6 cm/s), and IIEF-5 score (20.2 &plusmn, 3.6) compared to pre-treatment values. None of these endpoints showed significant change at T1 compared to T0 in patients of group B. Conclusions: Lt4 therapy is associated with an improvement of the erectile function at the vascular level, a decrease in MPV and total cholesterol. LT4 therapy should be considered in patients with arterial ED and SCH.