The environment and male reproductive system: the potential role and underlying mechanisms of cadmium in testis cancer.

Cadmium is a known human carcinogen, and has been shown to profoundly affect male reproductive function, at multiple levels, by exerting both endocrine and non-endocrine actions. Nevertheless, the potential role of cadmium in the etiology of testis cancer has been scantly investigated in humans, and, currently, available epidemiological observational studies are insufficient to draw definitive conclusions in this regard. On the contrary, experimental studies in laboratory animals demonstrated that cadmium is a strong inducer of testis tumors, mostly represented by benign Leydig cell adenoma; moreover, malignant transformation was also reported in few animals, following cadmium treatment. Early experimental studies in animals proposed an endocrine-dependent mechanism of cadmium-induced testis tumorigenesis; however, more recent findings from cell-free assays, in vitro studies, and short-term in vivo studies, highlighted that cadmium might also contribute to testis tumor development by early occurring endocrine-independent mechanisms, which include aberrant gene expression within the testis, and genotoxic effects, and take place well before the timing of testis tumorigenesis. These endocrine-independent mechanisms, however, have not been directly investigated on testis tumor samples retrieved from affected, cadmium-treated animals so far. The present review focuses on the relationship between cadmium exposure and testis cancer, by reporting the few epidemiological observational human studies available, and by providing animal-based experimental evidences of cadmium implication in the pathogenesis and progression of testis tumor. Moreover, the relevance of experimental animal studies to human cadmium exposure and the translational potential of experimental findings will be extensively discussed, by critically addressing strengths and weaknesses of available data.

Seminal cadmium affects human sperm motility through stable binding to the cell membrane.

Environmental pollutants are claimed to be major factors involved in the progressive decline of the fertility rate worldwide. Exposure to the heavy metal Cadmium (Cd) has been associated with reproductive toxicity due to its ionic mimicry. However, the possible direct accumulation of Cd in human sperm cells has been poorly investigated. In this study, we aimed to clarify the possible direct effect of Cd exposure on sperm function through the analysis of its cell accumulation. Semen samples from 30 male subjects residing in high environmental impact areas and adhering to the "Exposoma e Plurifocalità nella Prevenzione Oncologica" campaign for testis cancer prevention were compared with semen samples from 15 males residing in low exposure areas. Semen levels and cell Cd content were quantified by inductively coupled plasma (ICP) spectroscopy. Cell Cd distribution was assessed by scanning electron microscopy coupled with energy dispersive spectroscopy (SEM-EDS). The impact of Cd on sperm function was evaluated by the in vitro exposure to the heavy metal, whilst possible scavenging approaches/agents were assessed. In addition to higher values of semen Cd, exposed subjects showed a reduction in total motile sperm fraction compared to not-exposed controls (59.6% ± 13.6% vs. 66.3% ± 7.3%, p = 0.037). Semen Cd levels were also significantly correlated with SEM-EDS signals of Cd detected on the head and neck of sperm (respectively p = 0.738, p < 0.001 and ρ = 0.465, p < 0.001). A total of 2 h of in vitro exposure to 0.5 µM Cd was associated with a significant reduction of sperm progressive motility. Scavenging approaches with either hypo-osmotic swelling or 10 µM reduced glutathione were ineffective in blunting cell Cd and restoring motility. The reduction of exposure levels appears to be the main approach to reducing the reproductive issues associated with Cd.

Fertility in Acromegaly: A Single-Center Experience of Female Patients During Active Disease and After Disease Remission.

CONTEXT: Fertility represents a major concern in patients with acromegaly. OBJECTIVE: The current retrospective study aimed to investigate gonadal function and fertility rates in acromegalic women. METHODS: In this referral-center study, 50 acromegalic women with disease onset within reproductive age were evaluated for prevalence of gonadal dysfunction and infertility. Anthropometric, metabolic, hormonal parameters, and gynecological ultrasound were evaluated at diagnosis and after disease control. Data about menstrual disturbances, pregnancy, and polycystic ovarian morphology (PCOM) were investigated at disease onset, at diagnosis, and after disease control. RESULTS: At presumed disease onset, menstrual disturbances were reported in 32% of patients. Uterine leiomyoma, ovarian cysts, and PCOM were diagnosed in 18%, 12%, and 8%, respectively; 36.8% of patients were infertile. At diagnosis, menstrual disturbances were found in 58.1% (P = .02), being significantly more prevalent in patients with higher insulin-like growth factor-I quartiles (Q) (P = .03, Q1 vs Q4). Gynecological ultrasound revealed uterine leiomyoma, ovarian cysts, and PCOM in 39.1% (P = .04), 28.2% (P = .09), and 13% (P = .55), respectively. The infertility rate was 100% (P = .02). At disease control, menstrual disturbances were slightly decreased as compared to diagnosis (P = .09). Noteworthy, menstrual disturbances (P = .05) and particularly amenorrhea (P = .03) were significantly more frequent in patients with active disease duration greater than 5 years (median) as compared to those achieving disease control in less than 5 years. Among patients with pregnancy desire, 73.3% conceived at least once, with resulting infertility significantly decreased compared to diagnosis (26.7%; P = .01). At-term deliveries, preterm deliveries, and spontaneous abortions were recorded in 86.7%, 6.6%, and 6.6%, respectively, of the 15 pregnancies reported by the patients. No neonatal malformations and/or abnormalities were recorded. CONCLUSION: Gonadal dysfunction and infertility are common in acromegalic women within reproductive age, being directly influenced by disease status and/or duration.

Imaging of primary retroperitoneal neoplasms.

Retroperitoneal soft tissue tumors are frequently incidental findings on imaging tests as Computed tomography (CT) or Magnetic Resonance Imaging (MRI). Retroperitoneal soft tissue tumors are rare and therefore not common in daily radiological practice. Clinician and radiologist'skills to set retroperitoneal soft tissue tumors at presentation is crucial for a correct patient management. So far, several diagnostic algorithms have been proposed to assess retroperitoneal masses, which have not been validated by case histories (2-5). The aim of this article is to evaluate a new classification of retroperitoneal masses using CT and MRI. KEY WORDS: CT, Diagnosis, MRI, Retroperitoneum, Soft tissue sarcoma.

Vitamin D Reverts the Exosome-Mediated Transfer of Cancer Resistance to the mTOR Inhibitor Everolimus in Hepatocellular Carcinoma.

Several multi-kinase inhibitors were widely tested as potential first-line or second-line therapy in patients with advanced hepatocellular carcinoma (HCC). However, acquired drug resistance limits their clinical efficacy. Exosomes are microvesicles secreted by tumor and stromal cells that participate in many biological processes, including drug resistance. The current study evaluated the capability of exosomes derived from everolimus (EVE)-resistant HCC cells in inducing drug resistance in parental human HCC cells and the effect of 1,25(OH)2Vitamin D (VitD) treatment in restoring EVE sensitivity. The internalization of exosomes from EVE-resistant (EveR) cells into parental cells conferred the transmission of aggressive phenotype by promoting the transition of epithelial-to-mesenchymal phenotype, as demonstrated by immunofluorescence, and the acquisition of EVE resistance, as demonstrated by cell proliferation and colony formation assays. Moreover, the internalization of exosomes from EveR into parental cells induced deregulation of the mTOR pathway mainly by triggering the activation of the serine/threonine protein kinase Akt, involved in the cellular survival pathway, as demonstrated by Western blot analysis. Interestingly, the treatment with VitD prevented exosome-induced EVE resistance in HCC cells, significantly inhibiting cell proliferation but also partially reducing colony and size number when combined with EVE compared with control. In conclusion, the results of the current study demonstrated that exosomes derived from EveR cells could induce EVE resistance in EVE-sensitive HCC cells and that VitD can revert the exosome-induced EVE resistance by resensitizing to EVE treatment.

Effects of Pituitary Surgery and High-Dose Cabergoline Therapy on Metabolic Profile in Patients With Prolactinoma Resistant to Conventional Cabergoline Treatment.

Objective: Control of prolactin excess is associated with the improvement in gluco-insulinemic and lipid profile. The current study aimed at investigating the effects of pituitary surgery and medical therapy with high dose cabergoline (≥2mg/week) on metabolic profile in patients with prolactinoma resistant to cabergoline conventional doses (<2mg/week). Design: Thirty-four patients (22 men, 12 women, aged 33.9 ± 12.5 years) with prolactinoma (4 microadenomas and 30 macroadenomas) were included in the present study. Among them 17 (50%) received pituitary surgery (PS, Group1) and 17 (50%) medical therapy with high dose cabergoline (Group 2). Methods: In the whole patient cohort, anthropometric (weight, BMI) and biochemical (fasting glucose and insulin, triglycerides, total, HDL and LDL-cholesterol, HOMA-IR, HOMA-ß and ISI0) parameters were evaluated before and within 12 months after treatment. Results: In Group 1, prolactin (p=0.002), total cholesterol (p=0.012), and triglycerides (p=0.030) significantly decreased after pituitary surgery compared to the baseline. Prolactin significantly correlated with fasting glucose (r=0.056, p=0.025). In Group 2, fasting insulin (p=0.033), HOMA-ß (p=0.011) and ISI0 (p=0.011) significantly improved compared to baseline. Postoperative cabergoline dose significantly correlated with Δfasting glucose (r=-0.556, p=0.039) and ΔLDL cholesterol (r=- 0.521, p=0.046), and was the best predictor of ΔLDL cholesterol (r2 = 0.59, p=0.002) in Group 1. Conclusions: The rapid decrease in PRL levels induced by PS might improve lipid metabolism, whereas HD-CAB might exert a beneficial impact on both insulin secretion and peripheral sensitivity, thus inducing a global metabolic improvement.

Radium-223 Treatment in mCRPC Patient with Polycythemia Vera

There have been several studies on the clinical outcomes of Radium-223 treatment in patients with metastatic castration-resistant prostate cancer (mCRPC) who may have an increased risk of hematologic comorbidities. To the best of our knowledge, this is the first study to explore the potential bone marrow adverse effects (AEs) of Radium-223 administered with specific drugs used for hematologic conditions, such as polycythemia vera (PV). We report the case of a patient with mCRPC who was administered a combined treatment of Radium-223 and hydroxyurea for PV, aiming to support clinicians in predicting eventual AEs.

Clinical application of 18F-DOPA PET/TC in pediatric patients.

The use 18F-DOPA PET/CT for oncologic and non-oncologic pediatric diseases is well consolidated in clinical practice. The indications include brain tumors, neuroendocrine malignancies and congenital hyperinsulinism. The number of papers involving pediatric subjects is steadily growing. However, literature still lacks clinical trials and large multicentric studies in contrast with the extensive literature available for adult patients. The aim of this review is to discuss the main clinical indications of 18F-DOPA in pediatric oncologic and nononcologic diseases and to analyze its role in diagnosis, staging, biopsy and surgical planning. The high resolution of PET/CT tomographs in addition to the high sensitivity and specificity of 18F-DOPA imaging exceeds the downsides linked to this nuclear medicine imaging modality. In fact, few potential limitations could discourage the use of PET/CT imaging. For example, similarly to MRI studies the long acquisition time of a PET/CT scan often requires sedation especially in infants. Moreover, the radiation exposure of a PET/CT scan may be high, but the clinical benefit deriving from nuclear medicine imaging outruns the risk connected to the use of ionizing radiations.

Seminal Vesicle Urinary Reflux After TURP Mimicking Vesicular Invasion From Prostate Cancer on 18F-Choline PET/CT.

Seminal vesicles are paired secretory glands located posterior to the bladder in men that produce seminal fluid to maintain sperm. Seminal vesicle reflux into the prostatic ducts may be associated with prostatitis in older patients or may represent a very rare complication of transurethral prostate resection in patients with prostatic cancer. This condition is frequently accidentally diagnosed on excretory urography and/or retrograde urethrogram. Clinical presentation includes pain, fever, recurrent epididymitis-prostatitis, and post void dribbling.

Medical Treatment of Cushing's Disease: An Overview of the Current and Recent Clinical Trials.

Cushing's disease (CD) is a serious endocrine disorder characterized by chronic hypercortisolism, or Cushing's syndrome (CS), caused by a corticotroph pituitary tumor, which induces an excessive adrenocorticotropic hormone (ACTH) and consequently cortisol secretion. CD presents a severe clinical burden, with impairment of the quality of life and increase in mortality. Pituitary surgery represents the first-line therapy, but it is non-curative in one third of patients, requiring additional treatments. Among second-line treatments, medical therapy is gradually gaining importance, although the current medical treatments are unable to reach optimal efficacy and safety profile. Therefore, new drugs and new formulations of presently available drugs are currently under clinical investigation in international clinical trials, in order to assess their efficacy and safety in CD, or in the general population of CS. Among pituitary-directed agents, pasireotide, in the twice-daily subcutaneous formulation, has been demonstrated to be an effective treatment both in clinical trials and in real-world studies, and extension studies of the phase II and III clinical trials reported evidence of long-term efficacy with general good safety profile, although associated with frequent hyperglycemia, which requires monitoring of glucose metabolism. Moreover, the most recent once-monthly intramuscular formulation, pasireotide long-acting release (LAR), showed similar efficacy and safety, but associated with potential better compliance profile in CD. Roscovitine is an experimental drug currently under investigation. Among adrenal-directed agents, metyrapone is the only historical agent currently under investigation in a prospective, multicenter, international clinical trial, that would likely clarify its efficacy and safety in a large population of patients with CS. Osilodrostat, a novel agent with a mechanism of action similar to metyrapone, seems to offer a rapid, sustained, and effective disease control of CD, according to recently completed clinical trials, whereas levoketoconazole, a different chemical formulation of the historical agent ketoconazole, is still under investigation in clinical trials, with preliminary evidences showing an effective and safe control of CS. ATR-101 is an experimental drug currently under investigation. Among glucocorticoid receptor-directed drugs, mifepristone has been demonstrated to improve clinical syndrome and comorbidities, especially hypertension and impairment of glucose metabolism, but the occurrence of hypokalemia and in women uterine disorders, due to the concomitant action on progestin receptor, requires caution, whereas the preliminary evidence on relacorilant, characterized by high selectivity for glucocorticoid receptor, suggested good efficacy in the control of hypertension and impairment of glucose metabolism, as well as a good safety profile, in CS. Finally, a limited experience has demonstrated that combination therapy might be an interesting approach in the management of CD. The current review provides a summary of the available evidences from current and recent clinical trials on CD, with a specific focus on preliminary data.

The Interplay Between Prolactin and Reproductive System: Focus on Uterine Pathophysiology.

Over the last years, increasing evidence has focused on crucial pathogenetic role of PRL on malignant, premalignant and benign uterine diseases. Studies in animals and humans have documented that PRL receptors (PRL-Rs) are widely expressed on uterine cells and that PRL is directly synthesized by the endometrium under the stimulatory action of progesterone. Uterine PRL secretion is finely modulated by autocrine/paracrine mechanisms which do not depend on the same control factors implied in the regulation of PRL secretion from pituitary. On the other hand, PRL is synthesized also in the myometrium and directly promotes uterine smooth muscle cell growth and proliferation. Therefore, PRL and PRL-Rs appear to play an important role for the activation of signaling pathways involved in uterine cancers and preneoplastic lesions. Circulating PRL levels are reportedly increased in patients with cervical or endometrial cancers, as well as uterine premalignant lesions, and might be used as discriminative biomarker in patients with uterine cancers. Similarly, increased PRL levels have been implicated in the endometriosis-induced infertility, albeit a clear a causative role for PRL in the pathogenesis of endometriosis is yet to be demonstrated. This evidence has suggested the potential application of dopamine agonists in the therapeutic algorithm of women with malignant, premalignant and benign uterine lesions. This review focuses on the role of PRL as tumorigenic factor for uterus and the outcome of medical treatment with dopamine agonists in patients with malignant and benign uterine disease.

Role of Nuclear Imaging in Cardiac Amyloidosis Management: Clinical Evidence and Review of Literature.

Cardiac amyloidosis (CA) is an infiltrative disease characterized by the extracellular deposition of fibrils, amyloid, in the heart. The vast majority of patients with CA has one of two types between transthyretin amyloid (ATTR) and immunoglobulin light chain associated amyloid (AL), that have different prognosis and therapeutic options. CA is often underdiagnosed. The histological analysis of endomyocardial tissue is the gold standard for the diagnosis, although it has its limitations due to its invasive nature. Nuclear medicine now plays a key role in the early and accurate diagnosis of this disease, and in the ability to distinguish between the two forms. Recent several studies support the potential advantage of bone-seeking radionuclides as a screening technique for the most common types of amyloidosis, in particular ATTR form. This review presents noninvasive modalities to diagnose CA and focuses on the radionuclide imaging techniques (bone-seeking agents scintigraphy, cardiac sympathetic innervation and positron emission tomography studies) available to visualize myocardial amyloid involvement. Furthermore, we report the case of an 83-year old male with a history of prostate cancer, carcinoma of the cecum and kidney cancer, submitted to bone scan to detect bone metastasis, that revealed a myocardial uptake of 99mTC-HMPD suggestive of ATTR CA. An accurate and early diagnosis of CA able to distinguish beyween AL and ATTR CA combined to the improving therapies could improve the survival of patients with this disease.

Validation of the 3-variable prognostic score (3-PS) in mCRPC patients treated with 223Radium-dichloride: a national multicenter study.

OBJECTIVE: Radium-223 (223Ra) has been approved for treatment in patients with metastatic castration-resistant prostatic cancer (mCRPC) and bone metastasis. This α-emitting radionuclide has a beneficial effect on pain and is also capable to increase overall survival (OS). Several studies evaluated the prognostic value of different biomarkers at baseline, such as serum values, imaging parameters or pain. To date, however, clinicians lack a validated and simple system to assess which patients will most likely benefit from 223Ra treatment. The 3-variable prognostic score (3-PS), proposed in a single-center study in 2017 classifies patients in five prognostic groups with a specific OS. This study aims to validate the 3-PS in a larger multicenter population. METHODS: Four hundred and thirty mCRPC patients treated with 223Ra from six different centers were analyzed. The 3-PS score consists of the collection of baseline hemoglobin, prostatic specific antigen and Eastern cooperative oncology group performance status and was initially applied to the whole population (total group). The score was then validated on the 338 patient's subgroup (clean group) obtained by subtracting the 92 patients enrolled for the original study of the 3-PS score. This purified group served as further validation evidence. RESULTS: Statistical analysis showed that the 3-PS score was valid on the total group as well as in the clean group as the AUC estimated (0.74) falls within the CI of the AUC calculated on the validation sample (95% CI 0.66-0.82). CONCLUSION: This study confirms the validity of the 3-PS score for mCRPC patients. This score is simple, noninvasive and affordable and can be easily used to select patients that will most probably complete 223Ra treatment. In addition, this tool provides an exact estimate of life expectancy in terms of OS.

Vitamin D-Induced Molecular Mechanisms to Potentiate Cancer Therapy and to Reverse Drug-Resistance in Cancer Cells.

Increasing interest in studying the role of vitamin D in cancer has been provided by the scientific literature during the last years, although mixed results have been reported. Vitamin D deficiency has been largely associated with various types of solid and non-solid human cancers, and the almost ubiquitous expression of vitamin D receptor (VDR) has always led to suppose a crucial role of vitamin D in cancer. However, the association between vitamin D levels and the risk of solid cancers, such as colorectal, prostate and breast cancer, shows several conflicting results that raise questions about the use of vitamin D supplements in cancer patients. Moreover, studies on vitamin D supplementation do not always show improvements in tumor progression and mortality risk, particularly for prostate and breast cancer. Conversely, several molecular studies are in agreement about the role of vitamin D in inhibiting tumor cell proliferation, growth and invasiveness, cell cycle arrest and inflammatory signaling, through which vitamin D may also regulate cancer microenvironment through the activation of different molecular pathways. More recently, a role in the regulation of cancer stem cells proliferation and short non-coding microRNA (miRNAs) expression has emerged, conferring to vitamin D a more crucial role in cancer development and progression. Interestingly, it has been shown that vitamin D is able not only to potentiate the effects of traditional cancer therapy but can even contribute to overcome the molecular mechanisms of drug resistance-often triggering tumor-spreading. At this regard, vitamin D can act at various levels through the regulation of growth of cancer stem cells and the epithelial-mesenchymal transition (EMT), as well as through the modulation of miRNA gene expression. The current review reconsiders epidemiological and molecular literature concerning the role of vitamin D in cancer risk and tumor development and progression, as well as the action of vitamin D supplementation in potentiating the effects of drug therapy and overcoming the mechanisms of resistance often triggered during cancer therapies, by critically addressing strengths and weaknesses of available data from 2010 to 2020.

PET/CT in pediatric oncology.

The use of PET/CT in adult oncology has been consolidated by several and authoritative multicentric studies, metanalyses and systematic reviews. International guidelines help everyday nuclear medicine specialists, oncologists and radiologists in choosing the most suitable diagnostic path for each patient. Classifications based on traditional imaging and PET/CT findings define the most appropriate treatment and can predict the outcome for different types of malignancies. However, compared to adult patients the use of PET/CT in pediatric oncology is often burdened by lack of systematic and large multicentric studies and consequently accurate and precise guidelines. The cause of this shortage of large trials may be attributed to the rarity of these neoplasms and to the fear of long-term radiation effects on this peculiar category of patients. The aim of this article is to review the applications of PET/CT for imaging the most common pediatric neoplasms.

Smoke, alcohol and drug addiction and female fertility.

BACKGROUND: Considerable interest has been gathered on the relevant impact of preventable factors, including incorrect lifestyle and unhealthy habits, on female fertility. Smoking, alcohol and addictive drugs consumption represent a major concern, given the broad range of diseases which might be favored or exacerbated by these dependable attitudes. Despite the well-characterized effects of prenatal exposure on pregnancy outcomes and fetus health, a substantial proportion of women of reproductive age is still concerned with these habits. At present, the impact of smoke, alcohol and addictive drugs on women fertility, and, particularly, the specific targets and underlying mechanisms, are still poorly understood or debated, mainly due to the scarcity of well-designed studies, and to numerous biases. OBJECTIVE: The current review will provide a comprehensive overview of clinical and experimental studies in humans and animals addressing the impact of smoke, alcohol and addictive drugs on female fertility, by also embracing effects on ovary, oviduct, and uterus, with particular reference to primary endpoints such as ovarian reserve, steroidogenesis, ovulation and menstrual cycle, oviduct function and uterus receptivity and implantation. A brief focus on polycystic ovary syndrome and endometriosis will be also included. METHODS: A Pubmed literature search was performed with selected keywords; articles were individually retrieved by each author. No limitation was set for publication date. Articles in languages other than English were excluded. Additional articles were retrieved from references list of selected manuscripts. RESULTS AND CONCLUSIONS: Currently, the most consistent evidences of a detrimental effect of smoke, alcohol and addictive drugs on specific domains of the female reproductive function are provided by experimental studies in animals. Overall, clinical studies suggest that smoking is associated to decreased fertility, although causal inference should be further demonstrated. Studies addressing the effect of alcohol consumption on female fertility provide conflicting results, although the majority reported lack of a correlation. Extremely scarce studies investigated the effects of addictive drugs on female fertility, and the specific actions of selected drugs have been difficult to address, due to multidrug consumption.

Metabolic Disorders and Male Hypogonadotropic Hypogonadism.

Several studies highlight that testosterone deficiency is associated with, and predicts, an increased risk of developing metabolic disorders, and, on the other hand, is highly prevalent in obesity, metabolic syndrome and type-2 diabetes mellitus. Models of gonadotropin releasing hormone deficiency, and androgen deprivation therapy in patients with prostate cancer, suggest that hypogonadotropic hypogonadism might contribute to the onset or worsening of metabolic conditions, by increasing visceral adiposity and insulin resistance. Nevertheless, in functional hypogonadism, as well as in late onset hypogonadism, the relationship between hypogonadotropic hypogonadism and metabolic disorders is bidirectional, and a vicious circle between the two components has been documented. The mechanisms underlying the crosstalk between testosterone deficiency and metabolic disorders include increased visceral adipose tissue and insulin resistance, leading to development of metabolic disorders, which in turn contribute to a further reduction of testosterone levels. The decrease in testosterone levels might be determined by insulin resistance-mediated and, possibly, pro-inflammatory cytokine-mediated decrease of sex hormone binding globulin, resulting in a temporary increased free testosterone available for aromatization to estradiol in visceral adipose tissue, followed by a subsequent decrease in free testosterone levels, due to the excess of visceral adipose tissue and aromatization; by a direct inhibitory effect of increased leptin levels on Leydig cells; and by a reduced gonadotropin secretion induced by estradiol, inflammatory mediators, leptin resistance, and insulin resistance, with the ultimate determination of a substantial hypogonadotropic hypogonadism. The majority of studies focusing on the effects of testosterone replacement therapy on metabolic profile reported a beneficial effect of testosterone on body weight, waist circumference, body mass index, body composition, cholesterol levels, and glycemic control. Consistently, several interventional studies demonstrated that correction of metabolic disorders, in particular with compounds displaying a greater impact on body weight and insulin resistance, improved testosterone levels. The aim of the current review is to provide a comprehensive overview on the relationship between hypogonadotropic hypogonadism and metabolism, by clarifying the independent role of testosterone deficiency in the pathogenesis of metabolic disorders, and by describing the relative role of testosterone deficiency and metabolic impairment, in the context of the bidirectional relationship between hypogonadism and metabolic diseases documented in functional hypogonadotropic hypogonadism. These aspects will be assessed by describing metabolic profile in men with hypogonadotropic hypogonadism, and androgenic status in men with metabolic disorders; afterwards, the reciprocal effects of testosterone replacement therapy and corrective interventions on metabolic derangements will be reported.

Vitamin D reverts resistance to the mTOR inhibitor everolimus in hepatocellular carcinoma through the activation of a miR-375/oncogenes circuit.

Primary or acquired resistant mechanisms prevent the employment of individualized therapy with target drugs like the mTOR inhibitor everolimus (EVE) in hepatocellular carcinoma (HCC). The current study evaluated the effect of 1,25(OH)2Vitamin D (VitD) treatment on EVE sensitivity in established models of HCC cell lines resistant to everolimus (EveR). DNA content and colony formation assays, which measure the proliferative index, revealed that VitD pre-treatment re-sensitizes EveR cells to EVE treatment. The evaluation of epithelial and mesenchymal markers by western blot and immunofluorescence showed that VitD restored an epithelial phenotype in EveR cells, in which prolonged EVE treatment induced transition to mesenchymal phenotype. Moreover, VitD treatment prompted hepatic miRNAs regulation, evaluated by liver miRNA finder qPCR array. In particular, miR-375 expression was up-regulated by VitD in EveR cells, in which miR-375 was down-regulated compared to parental cells, with consequent inhibition of oncogenes involved in drug resistance and epithelial-mesenchymal transition (EMT) such as MTDH, YAP-1 and c-MYC. In conclusion, the results of the current study demonstrated that VitD can re-sensitize HCC cells resistant to EVE treatment triggering miR-375 up-regulation and consequently down-regulating several oncogenes responsible of EMT and drug resistance.

Air pollution and female fertility: a systematic review of literature.

Air pollution is a cause of concern for human health. For instance, it is associated with an increased risk for cancer, cardiovascular and respiratory disorders. In vitro and in vivo studies suggested that air pollutants could act as endocrine disruptors, promote oxidative stress and exert genotoxic effect. Whether air pollution affects female infertility is under debate. The aim of the present study was to conduct a systematic review of studies that evaluated the impact of air pollution on female infertility. We systematically searched the MEDLINE (PubMed) and SCOPUS databases to identify all relevant studies published before October 2017. No time or language restrictions were adopted, and queries were limited to human studies. We also hand-searched the reference lists of relevant studies to ensure we did not miss pertinent studies. The risk of bias and quality assessment of the studies identified were performed using the Newcastle-Ottawa Scale. Primary outcomes were conception rate after spontaneous intercourse and live birth rate after in vitro fertilization (IVF) procedures. Secondary outcomes were first trimester miscarriage, stillbirths, infertility, number of oocytes and embryo retrieved. Eleven articles were included in the analysis. We found that in the IVF population, nitrogen dioxide and ozone were associated with a reduced live birth rate while particulate matter of 10 mm was associated with increased miscarriage. Furthermore, in the general population, particulate matter of 2.5 mm and between 2.5 and 10 mm were associated with reduced fecundability, whereas sulfur dioxide, carbon monoxide and nitrogen dioxide might promote miscarriage and stillbirths. The main limitation of our findigns resides in the fact that the desegn of studies included are observational and retrospective. Furthermore, there was a wide heterogenity among studies. Although larger trials are required before drawing definitive conclusions, it seems that air pollution could represent a matter of concern for female infertility.

Smoke, alcohol and drug addiction and male fertility.

In recent decades, the decline in human fertility has become increasingly more worrying: while therapeutic interventions might help, they are vexing for the couple and often burdened with high failure rates and costs. Prevention is the most successful approach to fertility disorders in males and females alike. We performed a literature review on three of the most common unhealthy habits - tobacco, alcohol and drug addiction - and their reported effects on male fertility. Tobacco smoking is remarkably common in most first-world countries; despite a progressive decline in the US, recent reports suggest a prevalence of more than 30% in subjects of reproductive age - a disturbing perspective, given the well-known ill-effects on reproductive and sexual function as well as general health. Alcohol consumption is often considered socially acceptable, but its negative effects on gonadal function have been consistently reported in the last 30 years. Several studies have reported a variety of negative effects on male fertility following drug abuse - a worrying phenomenon, as illicit drug consumption is on the rise, most notably in younger subjects. While evidence in these regards is still far from solid, mostly as a result of several confounding factors, it is safe to assume that cessation of tobacco smoking, alcohol consumption and recreational drug addiction might represent the best course of action for any couple trying to achieve pregnancy.