Scope
Milk‐proteins, besides lactose, stimulate insulin and incretin secretion. Although whey‐proteins (WP) are more efficient than casein (Cas) in hormone secretion, the effects of reversal of the ...(WP/Cas) ratio in whole‐milk are poorly known.
Methods and Results
Healthy volunteers received two different cow‐milk drinks, at identical lactose (0.36 g × kg−1 BW) and total‐protein (0.18 g × kg1 BW) loads, but at reversed WP/Cas ratio. One is cow‐whole milk with a ≈20/80 WP/Cas ratio, the other an experimental cow‐milk with a ≈70/30 WP/Cas ratio (↑WP↓Cas‐milk). Both milk‐types induced the same mild hyperglycemic response. Following ↑WP↓Cas‐milk, the 20′–90′ insulin incremental area (iAUC) (+ ≈44%, p < 0.035), and the 20′–120′ C‐peptide iAUC (+ ≈47%, p < 0.015) are greater than those with cow‐milk. Similarly, following ↑WP↓Cas‐milk, the GLP‐1 20′–90′ iAUC (+96%, p < 0.025), and the GIP 30′–60′ iAUC (+140%, p < 0.006), were greater than those with cow‐milk. Plasma total and branched‐chain amino acids are also greater following the ↑WP↓Cas than cow‐milk.
Conclusions
Reversal of the (WP/Cas) ratio in cow‐milk enhanced the insulin response, an effect possibly mediated by incretins and/or amino acids(s). These data may be useful in designing specific milk formulas with different effects on insulin and incretin response(s).
The reversal of the WP/Cas ratio in cow milk at iso‐lactose and isoproteic loads, enhanced insulin and incretin secretion, possibly mediated by plasma total (and branched chain) response(s), and proportionally to the same extent of that of published studies using pure protein preparations, thus excluding a significant protein‐to‐protein interaction.
In this study we aimed to evaluate the effect on reproductive outcome of HPV vaccination in male subjects of infertile couples with HPV semen infection. In this single-center study, we ...retrospectively enrolled 151 infertile couples with detection of HPV in semen, attending our Hospital Unit of Andrology between January 2013 and June 2015, counseled to receive adjuvant HPV vaccination. Seventy-nine accepted vaccination (vaccine group) whilst 72 did not (control group). Our protocol of follow-up, aimed to evaluate HPV viral clearance, consisted in semen analysis, INNO-LiPA and FISH for HPV in semen cells after 6 and 12 months from basal evaluation. Spontaneous pregnancies, miscarriages and live births were recorded. Progressive sperm motility and anti-sperm antibodies were improved in the vaccine group at both time points (p < 0,05 vs control arm). Forty-one pregnancies, 11 in the control group and 30 in the vaccine group, were recorded (respectively 15% and 38,9%, p < 0,05) and resulted into 4 deliveries and 7 miscarriages (control group) and 29 deliveries and one miscarriage (vaccine group, p < 0,05 vs control group). HPV detection on sperms was predictive of negative pregnancy outcome. Adjuvant vaccination associated with enhanced HPV healing in semen cells and increased rate of natural pregnancies and live births.
Erectile dysfunction (ED) is a frequent microvascular complication of type 2 diabetes mellitus (T2DM). Hormonal derangements such as hypogonadism and hyperestrogenism are common in T2DM. Our aim was ...to investigate the relationship between estrogens and ED in diabetic patients.
We performed a retrospective study on 57 patients with T2DM suffering from ED. ED was assessed with the International Index of Erectile Function questionnaire (IIEF-5) and penile color-doppler ultrasound (PCDU). Blood tests included glycated hemoglobin, lipid profile, total testosterone (T), and estradiol (E2).
E2 was negatively correlated with IIEF-5 score after correction for age, diabetes duration, BMI, HbA1c, LDL- and HDL-cholesterol, T and PSA (r = −0.457, p < 0.01). Patients in the higher E2 quartile, had statistically higher probability of severe ED (61.5%). In the same patients, the PCDU demonstrated a statistically longer Acceleration Time (120.0 ± 24.5, p = 0.048) indicating an impaired arterial flow.
In diabetic patients, higher E2 is associated with worse erectile function and impaired cavernous arterial flow. Diabetic patients with high E2 are more prone to severe ED. It could be suggested to include estradiol measurement in the hormonal assessment of ED in patients with T2DM.
•Estrogen levels are correlated with erectile function in patients with type 2 diabetes.•In diabetic patients, hyperestrogenism is a risk factor for severe erectile dysfunction.•High estrogen levels may impair penile cavernous arterial flow independently of other cardiovascular risk factors.
GPRC6A is acknowledged as a major regulator of energy metabolism and male fertility through the action of undercarboxylated osteocalcin (ucOCN), representing a possible therapeutic target. We ...recently showed that the sex hormone-binding globulin (SHBG) binds to GPRC6A through the likely involvement of the 141-161 domain. To confirm this model, here we investigated the possible binding and agonist activity of SHBG(141-161) domain-peptide (SHBG
) on GPRC6A. The binding of SHBG
to GPRC6A and downstream dissociation from G
(GDP) protein was computationally modelled. SHBG
was obtained by solid-phase synthesis, characterized by circular dichroism (CD) and the receptor binding was assessed by displacement of ucOCN on HEK-293 cells transfected with GPRC6A gene. Agonist activity of SHBG
was assessed on Leydig MA-10 and Langerhans β-TC6 cell lines through the GPRC6A-mediated release of testosterone (T) and insulin. SHBG
was predicted to bind to GPRC6A and to reduce the affinity for G
(GDP) at computational level. Conformational properties and binding to GPRC6A of the synthetic SHBG
were confirmed by CD and displacement experiments. SHBG
stimulated cell secretion of T and insulin, with dose dependency from 10
to 10
M for T release (respectively P = 0,041 10
M; P = 0,032 10
M; P = 0,008 10
M vs basal) and for 10
to 10
M for insulin (respectively P = 0,041 10
M; P = 0,007 10
M; P = 0,047 10
M; P = 0,045 vs basal). Blockade with anti GPRC6A IgG abolished the response to SHBG
, suggesting agonist specificity. SHBG
showed stimulating activity on GPRC6A, representing a template peptide with possible therapeutic use for metabolic and endocrine disorders.
Bisphenols, and in particular bisphenol A (BPA), have been widely used for the production of plastic manufacts in the last 50 years. Currently, BPA is present in a variety of daily use polycarbonate ...plastics and epoxy resins, and dietary ingestion is considered the main route of human exposure. Accordingly, BPA is the chemical pollutant with the widest exposure in humans, involving nearly 90% of general population, according to recent studies. Concerns about BPA effects on human health date back to 1930s, when severe impact on male sexual development was suggested. Now, the acknowledged biological effects of BPA are various. In regard to human fertility, BPA has been shown to disrupt hormone signaling even at low concentrations. Results from human epidemiological studies have reported BPA interference with follicle stimulating hormone, inhibin B, estradiol, testosterone levels, and sexual function in male subjects. Moreover, recent studies have reported an association between BPA levels and reduced sperm concentration, motility, normal morphology, sperm DNA damage, and altered epigenetic pattern, resulting in trans-generational legacy of BPA effects. In this review, the recognized effects of BPA on male reproductive health are described, from the most recent issues on experimental models to epidemiological data. In addition, the very recent interest about the use of nutraceutical remedies to counteract BPA effects are discussed.
We analyzed the efficacy of penile low-intensity extracorporeal shockwave treatment for erectile dysfunction (ED) combined with cavernous artery disease (CAD). ED was evaluated by the International ...Index of Erectile Function, subdividing patients into mild and moderate/severe forms. CAD was assessed using penile color Doppler ultrasonography. Patients (n = 111) with a positive outcome after treatment, based upon the minimal clinically important difference of the International Index of ED, were followed up for 3 months and 6 months. We found a significant mean increase in the index of erectile function, with an overall improvement in hemodynamic parameters of the cavernous artery. In particular, 93.9% of the patients with mild ED without CAD responded to treatment and 72.7% resumed normal erectile function. Only 31.2% of the patients with moderate/severe ED and CAD responded to treatment, and none resumed normal erectile function. All patients with mild ED and no CAD maintained the effects of therapy after 3 months, while no patients with moderate/severe ED and CAD maintained the benefits of treatment after 3 months. Thus, patients with mild ED and no CAD have better and longer lasting responses to such treatment, with a higher probability of resuming normal erectile function than patients with moderate/severe ED and CAD.
During the last decade, the disclosure of systemic effects of osteocalcin (OCN) in its undercarboxylated form contributed to switch the concept of bone from a merely structural apparatus to a fully ...endocrine organ involved in the regulation of systemic functions. Since that time, the role of OCN as osteokine has been more and more widened appreciated and detailed by the major use of animal models, starting from the original function in the bone extracellular matrix as Gla-protein and spanning from the protective effects towards weight gain, insulin sensitivity and glucose homeostasis, to the anabolic and metabolic roles in skeletal muscle, to the stimulating effects on the testis endocrine function and male fertility, to the most recent preservation from anxious and depressive states through a direct activity on the central nervous system. In this review, experimental data supporting the inter-organ communication roles of this protein are discussed, together with the available data supporting the consistency between experimental data obtained in animals and those reported in humans. In addition, a specific session has been devoted to the possible significance the OCN as a template agonist on its receptor GPRC6A, for the development of novel therapeutic and pharmacological approaches for the treatment of dismetabolic states and male infertility.
Type V-phosphodiesterase-inhibitors (PDE5i) are the first choice drugs in the treatment of erectile dysfunction (ED), being effective in 60-70% of patients. However, approximately 50% of patients per ...year discontinue the treatment with PDE5i after reporting poor drug efficacy or major adverse drug reactions (ADR). To identify early markers of efficacy/safety for the treatment of ED with PDE5i, the basal clinical characteristics of patients, integrated with metabolomics analysis of serum and urine and genomic data, were here correlated with the PDE5i efficacy and the occurrence of ADR upon administration. Thirty-six males with new diagnosis of ED were consecutively recruited and characterized at baseline for anthropometrics, blood pressure, blood glucose, lipid profile, serum levels of thyroid/sex hormones and erectile function evaluated by IIEF-15 questionnaire. Targeted Next Generation Sequencing (NGS) was applied to genes involved in PDE5i pharmacodynamics and pharmacokinetics. Fasting metabolic profiles of serum and urine were assessed by nuclear magnetic resonance (NMR)-based metabolomics analysis. Patients were prescribed on-demand therapy with Sildenafil oro-dispersible film and followed-up after 3 months from recruitment. Baseline data were compared with IIEF-15 score at follow-up and with the occurrence of ADR recorded by a dedicated questionnaire. Twenty-eight patients were finally included in the analysis. Serum LDL-cholesterol levels were increased in those reporting ADR (143.3 ± 13.2 mg/dl ADR vs. 133.1 ± 12.4 mg/dl No ADR;
= 0.046). NGS data showed that specific variants of
and
genes were more represented in drug responders (both relative risk = 2.7 0.9-5.1;
= 0.04). NMR-based metabolomics showed the highest association between serum LDL-cholesterol metabolites and the occurrence of ADR (Hazard ratio = 17.5;
= 0.019). The association between lipid profile and the ADR pattern suggests major cues in the tailoring of ED therapy with PDE5i.
Background: Weight control through lifestyle interventions represents a suitable strategy to avoid the metabolic, endocrine, and reproductive comorbidities associated with overweight and obesity. ...Reduced testosterone (T) levels are a worsening factor in overweight males. However, prognostic parameters of long-term weight loss are not readily available. Here, we tested the prognostic value of early variations of anthropometric and hormonal parameters, with a focus on ultrasound stratigraphy (US) and the reduction in body mass index (BMI) associated with nutritional counseling/lifestyle interventions at 6-month follow-up. Methods: Ninety-five male subjects (BMI 25–34.9 kg/m 2 ) who had undergone nutritional/lifestyle interventions, were retrospectively analyzed for: body weight and composition; US evaluation at the triceps (TRC), abdominal (ABD), and thigh (THI) areas; and circulating levels of T, luteinizing hormone, and follicle-stimulating hormone. Sixty patients (63.2%) completed the 6-month follow-up program. Results: At 6 months, a significant reduction in BMI (26.38 ± 1.55 vs. 31.5 ± 5.0 basal, p < 0.001) and increase in T levels (18 ± 5.4 vs. 9.5 ± 2.3 nmol/L basal, p = 0.04) were observed. Subjects in the highest quartile of the BMI reduction at 6 months (ΔBMI 6 mo), compared to the lowest, showed a significant difference at the 2-month follow-up variation of BMI (p = 0.025), and fat and muscle thickness at the TRC (both p < 0.001) and ABD (p < 0.001 and p = 0.002, respectively) areas. Variation of TRC muscle thickness at 2 months was the only independent predictor of ΔBMI 6 mo in the multiple stepwise regression analysis. Conclusions: BMI evaluation and US represent useful monitoring tools in the follow-up of nutritional/lifestyle interventions for overweight-to-mildly obese patients. The important effects on motivation and adherence to the intervention program are to be considered.
Type 5 phosphodiesterase inhibitors (PDE5i) are efficient drugs used for treatment of erectile dysfunction (ED); however, a large discontinuation rate due to major side effects is reported. The aim ...of this study was to evaluate the possible improvement of sildenafil (Sild) pharmacokinetics associated to the sublingual administration of the new available oro-dispersible film (ODF), compared to both the oro-dispersible tablet (ODT) and the film-coated tablet (FCT) as original
formulation.
disaggregation test, dissolution test, and permeation test in specific devices to estimate the trans-mucosal absorption.
analysis of serum Sild levels, by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), was performed in 20 patients with psychogenic ED receiving alternatively
FCT or sublingual ODT or ODF, at an equal dosage (50 mg). Pharmacokinetic parameters of Sild and adverse drug reactions experienced after the dosing of each formulation were compared.
, ODF showed the highest time to disaggregation and an increased rate of permeation compared to both ODT and FCT (
= 0.017 and
= 0.008, respectively).
, compared to both FCT and ODT, ODF showed a faster increase of serum Sild levels (serum levels at 15 min from dosing, respectively: 2.24 ± 1.4 ng/ml FCT, 0.5 ± 0.3 ng/ml ODT, and 13.5 ± 9.1 ng/ml ODF;
< 0.01 and
< 0.05 vs. ODF) together with a higher drug bioavailability within 60 min from dosing (relative AUC
vs. FCT, respectively: 100.0 ± 44.9% FCT, 183.8 ± 75.4% ODT, and 304.2 ± 156.0% ODF). A trend toward lower peak serum levels was observed for ODF. Finally, ODF showed a lower prevalence of headache compared to FCT (1 vs. 35%;
< 0.05) and improved pattern of flushing and nasal congestion.
Sublingual Sild ODF improves the drug tolerability through a likely modified pharmacokinetic, suggesting a possible implication also in the clinical efficacy profile. Sublingual administration of oro-dispersible formulations may represent a strategy to ameliorate the adherence to therapy with PDE5i, particularly in patients discouraged by side effects.
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