Obesity and Male Infertility: True, True, and Unrelated?

While the prevalence of obesity has rapidly increased worldwide, there has also been a notable decline in semen parameters over the last several decades. While obesity can negatively impact reproductive hormones, many studies have sought a link between rising obesity and decreased male fertility potential. Nonetheless, few data support a direct link between the two. The focus on obesity as a causative factor in male infertility can potentially result in patient harm through delayed fertility treatment and missed diagnoses. This review investigates the associations between obesity and male infertility and why a potential direct link has been elusive and may not exist. Additionally, indirect mechanisms that may link the two will be reviewed and treatment options for obese infertile men presenting for evaluation will briefly be discussed.

The contribution of the immune system to genitourinary fibrosis.

Fibrotic diseases of the genitourinary tract are devastating and incompletely understood pathologies. These diseases include urethral and ureteral strictures, retroperitoneal fibrosis, and Peyronie's disease. They can contribute to obstructive uropathy and sexual dysfunction. Poor understanding of the pathophysiology of these diseases severely limits our ability to prevent and treat them. Genitourinary fibrotic diseases likely represent related pathologies that share common underlying mechanisms involving wound healing in response to injury. These diseases share the common feature of extracellular matrix abnormalities-such as collagen deposition, transforming growth factor-ß accumulation, and dysregulation of collagen maturation-leading to abnormal tissue stiffness. Given the association of many of these diseases with autoimmunity, a systemic pro-inflammatory state likely contributes to their associated fibrogenesis. Herein, we explore the immunologic contribution to fibrogenesis in several fibrotic diseases of the genitourinary system. Better understanding how the immune system contributes to fibrosis in these diseases may improve prevention and therapeutic strategies and elucidate the functions of immunologic contributors to fibrosis in general.

Peyronie's disease: is it genetic or not?

Peyronie's disease (PD) is a devastating disease that affects up to 13% of adult men. While trauma to the erect penis is common prior to onset, it is clear that trauma alone is not sufficient to cause PD. Over the past 40 years, multiple lines of evidence have pointed to a genetic factor that predisposes some men to develop PD. Despite dramatic technological advances in the field of genetics, we have made little progress in identifying the genetic contributors to the disease. This review will critically evaluate the literature concerning the genetics of PD published to date. Particular focus will be placed on study design as much of the data are contradictory yet may still give some insight into the etiology of PD. The challenges in identifying the genetic underpinnings of PD will be discussed along with the potential mechanisms that can overcome these challenges.

Where are we going with gene screening for male infertility?

Male infertility is a heterogenous disease process requiring the proper functioning and interaction of thousands of genes. Given the number of genes involved, it is thought that genetic causes contribute to most cases of infertility. Identifying these causes, however, is challenging. Infertility is associated with negative health outcomes, such as cancer, highlighting the need to further understand the genetic underpinnings of this condition. This paper describes the genetic and genomic tests currently available to identify the etiology of male infertility and then will discuss emerging technologies that may facilitate diagnosis and treatment of in the future.

Sperm cryopreservation of transgender individuals: trends and findings in the past decade.

OBJECTIVES: Awareness and acceptance of transgenderism have increased in the last two decades. There is limited literature regarding the incidence and semen characteristics of transwomen banking spermatozoa. We sought to assess the incidence of sperm cryopreservation of transgender individuals compared with the cisgender population in the last 10 years. Semen parameters were also compared between the two groups. MATERIALS AND METHODS: We performed a retrospective analysis of sperm cryopreservation performed at a single center from 2006 through 2016. Using available data on indications for banking and prior hormonal therapy status, we isolated healthy transgender and cisgender cohorts for semen parameter comparison. Linear regression was used to compare the incidence trends. Semen parameters were compared using the generalized estimating equations method. The rates of semen parameter abnormality of each group were compared using chi-square test. Semen parameter abnormalities were defined using WHO 2010 reference values. RESULTS: We analyzed 194 transgender samples and 2327 cisgender samples for a total of 84 unique transgender sperm bankers and 1398 unique cisgender sperm bankers. The number of transgender sperm bankers increased relative to cisgender sperm bankers from 2006 to 2016. Following exclusion of cisgender sperm bankers with health issues that might impact semen quality and transgender sperm bankers with known prior hormonal therapy, we compared the semen parameters of 141 healthy cisgender sperm bankers and 78 healthy transgender sperm bankers. The transgender sperm bankers demonstrated lower sperm concentration, total motile sperm count, and post-thaw sperm parameters. The transgender sperm bankers also demonstrated a higher incidence of oligozoospermia. CONCLUSIONS: This is the largest report to date on the incidence of transgender sperm cryopreservation and comparison of semen characteristics with cisgender sperm bankers. The data reveal an increased incidence of transgender sperm banking as well as poorer semen parameters of transgender individuals compared with cisgender controls.

Iron and a Man's Reproductive Health: the Good, the Bad, and the Ugly.

PURPOSE OF REVIEW: To discuss the physiologic and pathologic effects of iron on men's reproductive health. RECENT FINDINGS: Iron overload diseases are associated with hypogonadotropic hypogonadism, infertility, and sexual dysfunction in men. Recent findings have elucidated the roles by which iron may affect the male reproductive axis. Iron is requisite for life. Iron can also catalyze the production of reactive oxygen species. To maintain balance, the human body tightly regulates dietary iron absorption. Severe iron overload disorders-e.g., hereditary hemochromatosis and ß-thalassemia-occur when these regulatory mechanisms are deficient. While iron is necessary, the male reproductive system is particularly sensitive to iron overload. Hypogonadotropic hypogonadism, infertility, and sexual dysfunction commonly occur if excess iron from iron overload disorders is not removed. The average male in the USA consumes significantly more iron than needed to replace daily losses. How this degree of iron loading may affect one's reproductive health remains less clear, but there is evidence it may have adverse effects.

Penile Rehabilitation: The "Up"-date.

PURPOSE OF REVIEW: The purpose of this review is to review the penile rehabilitation literature published since the beginning of 2017. Specific emphasis was placed on determining how the new findings increase our understanding of the mechanisms leading to recovery of erectile function after pelvic surgery and to identify potential focus areas for future studies. RECENT FINDINGS: A meta-analysis of penile rehabilitation after prostatectomy was published in early 2017 reporting that PDE-5 inhibitors, intracavernosal injection (ICI) therapy and vacuum erection devices (VED) improved erectile function; however, the benefit was not observed after a washout period. Preclinical studies have identified potential regenerative therapies after cavernous nerve injury. SUMMARY: While significant methodological challenges remain, recent literature suggests benefits to starting penile rehabilitation immediately after surgery, but not extending past 1 year post-operatively. The cost-benefit ratio of penile rehabilitation remains unclear; however, decreasing costs of PDE-5 inhibitors as well as improvements in characterizing post-surgical erectile dysfunction may help to personalize penile rehabilitation, improve outcomes and improve the cost-benefit ratio. Better and more consistent trial design is needed to develop the optimal regimen(s) for restoring sexual function in men. Finally, future studies to translate promising preclinical regeneration therapies to humans are also needed.

Chronic exposures and male fertility: the impacts of environment, diet, and drug use on spermatogenesis.

Several recent studies have suggested that sperm concentrations and semen quality have been decreasing over the past several decades in many areas of the world. The etiology of these decreases is currently unknown. Acute events can have significant impacts on spermatogenesis and are often readily identified during the male fertility evaluation. The majority of male factor infertility, however, is idiopathic. Chronic, low-dose exposures to chemicals and nutrients are more difficult to identify, but are extremely prevalent. These exposures have been shown to have dramatic effects on both individual and community health and interest in the cumulative and synergistic impacts of such agents on spermatogenesis has been increasing. While our understanding of these potential hazards is evolving, it is clear that they may significantly influence male reproductive potential. This review explores the literature related to effects of chronic exposures from drug use, dietary intake, and the environment on spermatogenesis in humans and animals.

Adipocyte iron regulates leptin and food intake.

Dietary iron supplementation is associated with increased appetite. Here, we investigated the effect of iron on the hormone leptin, which regulates food intake and energy homeostasis. Serum ferritin was negatively associated with serum leptin in a cohort of patients with metabolic syndrome. Moreover, the same inverse correlation was observed in mice fed a high-iron diet. Adipocyte-specific loss of the iron exporter ferroportin resulted in iron loading and decreased leptin, while decreased levels of hepcidin in a murine hereditary hemochromatosis (HH) model increased adipocyte ferroportin expression, decreased adipocyte iron, and increased leptin. Treatment of 3T3-L1 adipocytes with iron decreased leptin mRNA in a dose-dependent manner. We found that iron negatively regulates leptin transcription via cAMP-responsive element binding protein activation (CREB activation) and identified 2 potential CREB-binding sites in the mouse leptin promoter region. Mutation of both sites completely blocked the effect of iron on promoter activity. ChIP analysis revealed that binding of phosphorylated CREB is enriched at these two sites in iron-treated 3T3-L1 adipocytes compared with untreated cells. Consistent with the changes in leptin, dietary iron content was also directly related to food intake, independently of weight. These findings indicate that levels of dietary iron play an important role in regulation of appetite and metabolism through CREB-dependent modulation of leptin expression.

Gene expression profiling in subcutaneous, visceral and epigastric adipose tissues of patients with extreme obesity.

OBJECTIVE: The goal of the present study was to identify differences in gene expression between SAT, VAT and EAT depots in Class III severely obese individuals. DESIGN: Human subcutaneous (SAT) and visceral (VAT) adipose tissues exhibit differential gene expression profiles. There is little information, however, about the other proximal white adipose tissue, epigastric (EAT), in terms of its function and contribution to metabolism. SUBJECTS AND METHODS: Using RNA from adipose biospecimens obtained from Class III severely obese patients undergoing open Roux-en-Y gastric bypass surgery, we compared gene expression profiles between SAT, VAT and EAT, using microarrays validated by real-time quantitative PCR. RESULTS: The three depots were found to share 1907 genes. VAT had the greatest number of genes (66) expressed exclusively in this depot, followed by SAT (23), and then EAT (14). Moreover, VAT shared more genes with EAT (65) than with SAT (38). Further analyses using ratios of SAT/EAT, VAT/EAT and SAT/VAT identified specific as well as overlapping networks and pathways of genes representing dermatological diseases, inflammation, cell cycle and growth, cancer and development. Targeted analysis of genes, having a role in adipose tissue development and function, revealed that Peroxisome proliferator-activated receptor Gamma Coactivator 1-alpha (PGC1-α) that regulates the precursor of the hormone Irisin (FNCD5) were abundantly expressed in all three fat depots, along with fibroblast growth factors (FGF) FGF1, FGF7 and FGF10, whereas, FGF19 and FGF21 were undetectable. CONCLUSIONS: These data indicate that EAT has more in common with VAT, suggesting similar metabolic potential. The human epigastric adipose depot could have a significant functional role in metabolic diseases and should be further investigated.

Adipocyte iron regulates adiponectin and insulin sensitivity.

Iron overload is associated with increased diabetes risk. We therefore investigated the effect of iron on adiponectin, an insulin-sensitizing adipokine that is decreased in diabetic patients. In humans, normal-range serum ferritin levels were inversely associated with adiponectin, independent of inflammation. Ferritin was increased and adiponectin was decreased in type 2 diabetic and in obese diabetic subjects compared with those in equally obese individuals without metabolic syndrome. Mice fed a high-iron diet and cultured adipocytes treated with iron exhibited decreased adiponectin mRNA and protein. We found that iron negatively regulated adiponectin transcription via FOXO1-mediated repression. Further, loss of the adipocyte iron export channel, ferroportin, in mice resulted in adipocyte iron loading, decreased adiponectin, and insulin resistance. Conversely, organismal iron overload and increased adipocyte ferroportin expression because of hemochromatosis are associated with decreased adipocyte iron, increased adiponectin, improved glucose tolerance, and increased insulin sensitivity. Phlebotomy of humans with impaired glucose tolerance and ferritin values in the highest quartile of normal increased adiponectin and improved glucose tolerance. These findings demonstrate a causal role for iron as a risk factor for metabolic syndrome and a role for adipocytes in modulating metabolism through adiponectin in response to iron stores.

Pediatric urinary stone composition in the United States.

PURPOSE: The incidence of urolithiasis in children is increasing. However, stone composition studies in this population are limited. We sought to determine the effects of age, gender and geographical location on urinary stone composition in the United States pediatric population. MATERIALS AND METHODS: We obtained composition analyses for all urinary stones submitted to a reference laboratory between 2000 and 2009. Stones were excluded if the patient was younger than 1 year or older than 18 years. Stone composition was determined by Fourier transform infrared spectroscopy. Logistic regression analysis was performed to determine associations between stone composition frequency and age, gender and geographical region. RESULTS: A total of 5,245 stones were included in our analysis. Calcium was found in 89.2% of stones. The percentage of stones containing calcium oxalate increased, while magnesium ammonium phosphate and ammonium acid urate containing stones decreased with age. Calcium oxalate and magnesium ammonium phosphate containing stones were more common in females, while uric acid stones were more common in males. Additionally, significant differences in stone composition frequency were noted between males and females in specific age groups and between age groups within the same gender. Geographical distribution was not significantly associated with stone composition. CONCLUSIONS: This series is the largest analysis to date of urinary stone composition in the pediatric population in the United States. Age and gender were significantly associated with stone composition, while geographical region was not significantly associated with stone composition.

Regulation of Akt signaling by O-GlcNAc in euglycemia.

The hexosamine biosynthesis pathway (HBP) regulates the posttranslational modification of nuclear and cytoplasmic protein by O-linked N-acetylglucosamine (O-GlcNAc). Numerous studies have demonstrated that, in hyperglycemic conditions, excessive glucose flux through this pathway contributes to the development of insulin resistance. The role of the HBP in euglycemia, however, remains largely unknown. Here we investigated the effect of O-GlcNAc on hepatic Akt signaling at physiological concentrations of glucose. In HepG2 cells cultured in 5 mM glucose, removal of O-GlcNAc by adenoviral-mediated overexpression of O-GlcNAcase increased Akt activity and phosphorylation. We also observed that Akt was recognized by succinylated wheat germ agglutinin (sWGA), which specifically binds O-GlcNAc. Overexpression of O-GlcNAcase in HepG2 cells reduced the levels of Akt in sWGA precipitates. The increased Akt activity was accompanied by increased phosphorylation of Akt substrates and reduced mRNA for glucose-6-phosphatase and phosphoenolpyruvate carboxykinase (PEPCK). The increased Akt activity was not a result of activation of its upstream activator phosphoinositide 3-kinase (PI 3-kinase). Further demonstrating Akt regulation by O-GlcNAc, we found that overexpression of O-GlcNAcase in the livers of euglycemic mice also significantly increased Akt activity, resulting in increased phosphorylation of downstream targets and decreased mRNA for glucose-6-phosphatase. Together, these data suggest that O-GlcNAc regulates Akt signaling in hepatic models under euglycemic conditions.

Increased glucose disposal and AMP-dependent kinase signaling in a mouse model of hemochromatosis.

Hereditary hemochromatosis is an inherited disorder of increased iron absorption that can result in cirrhosis, diabetes, and other morbidities. We have investigated the mechanisms underlying supranormal glucose tolerance despite decreased insulin secretion in a mouse model of hemochromatosis with deletion of the hemochromatosis gene (Hfe(-/-)). Hfe(-/-) mice on 129Sv or C57BL/6J backgrounds have decreased glucose excursions after challenge compared with controls. In the C57BL/6J/ Hfe(-/-), for example, incremental area under the glucose curve is reduced 52% (p < 0.001) despite decreased serum insulin, and homeostasis model assessment insulin resistance is decreased 50% (p < 0.05). When studied by the euglycemic clamp technique 129Sv/Hfe(-/-) mice exhibit a 20% increase in glucose disposal (p < 0.05) at submaximal insulin but no increase at maximal insulin compared with wild types. [1,2-(13)C]D-glucose clearance from plasma is significantly increased in Hfe(-/-) mice (19%, p < 0.05), and lactate derived from glycolysis is elevated 5.1-fold in Hfe(-/-) mice (p < 0.0001). Basal but not insulin-stimulated glucose uptake is elevated in isolated soleus muscle from Hfe(-/-) mice (p < 0.03). Compared with controls Hfe(-/-) mice exhibit no differences in serum lipid, insulin, glucagon, or thyroid hormone levels; adiponectin levels are elevated 41% (p < 0.05), and the adiponectin message in adipocytes is increased 83% (p = 0.04). Insulin action measured by phosphorylation of Akt is not enhanced in muscle, but phosphorylation of AMP-dependent kinase is increased. We conclude that supranormal glucose tolerance in iron overload is characterized by increased glucose disposal that does not result from increased insulin action. Instead, the Hfe(-/-) mice demonstrate increased adiponectin levels and activation of AMP-dependent kinase.

Molecular basis for RNA kink-turn recognition by the h15.5K small RNP protein.

The interaction between box C/D small nucleolar (sno)RNAs and the 15.5K protein nucleates snoRNP assembly. Many eukaryotic snoRNAs contain two potential binding sites for this protein, only one of which appears to be utilized in vivo. The binding site conforms to the consensus for a kink-turn motif. We have investigated the molecular basis for selection of one potential site over the other using in vitro mobility shift assays and nucleotide analog interference mapping of Xenopus U25 snoRNA and of a circularly permuted form. We find that preferential binding of human 15.5K is not dependent on the proximity of RNA ends, but instead appears to require a structural context beyond the kink-turn itself. Direct analysis of the energetic contributions to binding made by 18 functional groups within the kink-turn identified both backbone atoms and base functionalities as key for interaction. An intramolecular RNA-RNA contact via a 2'-hydroxyl may supercede a putative Type I A-minor interaction in stabilizing the RNA-protein complex.

Buckminsterfullerenol free radical scavengers reduce excitotoxic and apoptotic death of cultured cortical neurons.

Novel anti-oxidants based on the buckminsterfullerene molecule were explored as neuroprotective agents in cortical cell cultures exposed to excitotoxic and apoptotic injuries. Two polyhydroxylated C60 derivatives, C60(OH)n, n = 12, and C60(OH)nOm, n = 18-20, m = 3-7 hemiketal groups, demonstrated excellent anti-oxidant capabilities when tested by electron paramagnetic spectroscopy with a spin-trapping agent and a hydroxyl radical-generating system. These water-soluble agents decreased excitotoxic neuronal death following brief exposure to NMDA (by 80%), alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA; by 65%), or kainate (by 50%). Electrophysiology and tracer 45Ca(2+)-uptake studies verified that buckminsterfullerenois are not NMDA or AMPA/kainate receptor antagonists. Buckminsterfullerenols also reduced neuronal apoptosis induced by serum deprivation. These results support the idea that oxidative stress contributes to both excitotoxic and apoptotic neuronal death, and furthermore suggest that fullerenols represent a novel type of biological anti-oxidant compound.

Amebic meningoencephalitis caused by Balamuthia mandrillaris.

Free-living amebae etiologically associated with central nervous system (CNS) infection in children have included Acanthamoeba, Naegleria, and recently, leptomyxid ameba. Two previously healthy children are reported with CNS infection caused by leptomyxid ameba, recently classified as Balamuthia mandrillaris. One child, a 27-month-old boy, had right hemiparesis and aphasia, and the other, a 13-year-old girl, had headache, right hemiparesis, diplopia, and left facial weakness. Cerebrospinal fluid studies of both children revealed a mononuclear pleocytosis and mildly elevated protein. The younger child developed seizures and progressive cerebrovascular occlusions; both developed hydrocephalus and coma progressing to death 16 days after onset of symptoms. The younger child at autopsy had necrotizing meningoencephalitis, left internal carotid arteritis, and amebic trophozoites and cysts in brain. Perivascular trophozoites were difficult to distinguish morphologically from macrophages in the older child, who had no cyst forms. Indirect immunofluorescence test revealed CNS infection with B. mandrillaris in both. This leptomyxid ameba, formerly considered an innocuous soil organism, should be considered in the differential diagnosis of progressive or atypical childhood stroke.