Safety, pharmacokinetics, and pharmacodynamics of SHR7280, an oral gonadotropin-releasing hormone receptor antagonist, in healthy men: a randomized, double-blind, placebo-controlled phase 1 study.

BACKGROUND: Gonadotropin-releasing hormone (GnRH) antagonists are a promising therapeutic approach for treating hormone-dependent prostate cancer. Currently, the mainstream GnRH antagonists are polypeptide agents administered through subcutaneous injection. In this study, we evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SHR7280, an oral small molecule GnRH antagonist, in healthy men. METHODS: This phase 1 trial was a randomized, double-blind, placebo-controlled, and dose-ascending study. Eligible healthy men were randomized in a 4:1 ratio to receive either oral SHR7280 tablets or placebo twice daily (BID) for 14 consecutive days. The SHR7280 dose was initiated at 100 mg BID and then sequentially increased to 200, 350, 500, 600, 800, and 1000 mg BID. Safety, PK, and PD parameters were assessed. RESULTS: A total of 70 subjects were enrolled and received the assigned drug, including 56 with SHR7280 and 14 with placebo. SHR7280 was well-tolerated. The incidence of adverse events (AEs, 76.8% vs 85.7%) and treatment-related AEs (75.0% vs 85.7%), as well as the severity of AEs (moderate AEs, 1.8% vs 7.1%) were similar between the SHR7280 group and placebo group. SHR7280 was rapidly absorbed in a dose-dependent manner, with a median Tmax of each dose group ranging from 0.8 to 1.0 h on day 14 and a mean t1/2 ranging from 2.8 to 3.4 h. The PD results demonstrated that SHR7280 exhibited a rapid and dose-proportional suppression of hormones, including LH, FSH, and testosterone, with maximum suppression achieved at doses of 800 and 1000 mg BID. CONCLUSIONS: SHR7280 showed an acceptable safety profile, as well as favorable PK and PD profiles within a dose range of 100 to 1000 mg BID. This study proposes a rationale for further investigation of SHR7280 as a potential androgen deprivation therapy. TRIAL REGISTRATION: Clinical trials.gov NCT04554043; registered September 18, 2020.

Need for age-specific prostate-specific antigen reference intervals in a Nigerian population.

Background: In Nigeria, the diagnostic value of prostate-specific antigen (PSA) is a matter of debate. PSA levels are known to vary with population, environmental factors, and advancing age. Studies suggest age-specific reference intervals (ASRIs) of PSA value are more accurate than single cut-off PSA value. For ASRIs to be used effectively, reference intervals (RIs) must be fully evaluated. Aim: We determine ASRIs in a Nigerian population. Materials and Methods: The study was carried out from January 2016 to January 2019 among 660 adult Nigerian men aged 30-86 years old in Enugu State. Participants completed questionnaire demographics and previous screening. Age group was the indicator. Among them, a total 24 (3.6%) were excluded. Data from 636 (96.4%) men were analyzed for ASRIs. Estimation of PSA was done as per the International Federation of Clinical Chemistry Guideline. Spearman correlation was used to identify correlates P values < 0.05 which was considered significant. Results: The mean age group was 49.6 ± 10.2 years. ASRIs using 95th percentile, and PSA values in each 10 years groups were 0-1.94 ng/ml (median 0.22), 0-2.52 ng/ml (median 0.42), 0-3.52 ng/ml (median 1.06), 0-4.8 ng/ml (median 2.1), 0-6.95 ng/ml (median 4.1), and 0-5.6 ng/ml (median 2.4), for age groups 30-39, 40-49, 50-59, 60-69, 70-79, and ≥80 years, respectively. There was positive correlation between PSA and age (r = 0.9915, P < 0.0001). Low income and educational background were more prevalent among the study group. Conclusion: Our study provided the ASRIs in our environment but higher than single cut-off value. The data recommended PSA values should be characterized by age and ethnicity.

Whole-body cryostimulation does not disturb the homeostasis of the system in physically active men - Pilot study.

Whole-body cryostimulation (W-BC) is commonly used following exercise to accelerate recovery or as a form of therapy to prevent and cure sports injuries. This study aimed to investigate the effect of a series of 24 W-BC sessions on morphological and rheological blood indicators in physically active men. Eighteen physically active men participated in the study (mean age 22.1 ± 0.07). They were divided into two groups depending on their self-reported levels of physical activity: moderate or high physical activity. The participants completed a total of 24 W-BC sessions every second day, over a span of two months. Blood was collected at baseline, immediately after and 24 h after the first treatment, before and after the 12th treatment, before, immediately after, and 24 h after the 24th treatment, and one, two, three, and four weeks after the 24th treatment. Rheological and morphological indicators of blood were examined. The number of leukocytes was decreased in the moderate activity group (p < 0.05) but not in the high intensity group, following the first W-BC session. There were no significant changes in elongation index (EI) at a shear stress of 2.19-31.04 (Pa) in both groups as well as at the following values: aggregation index (AI), the half time (T½) and the amplitude of aggregation (AMP) in both studied groups. Differences between the first and the 12th or the 24th session became apparent in some morphological indices in one or both groups. Changes in the morphological properties were not observed after the first exposure but became evident following repeated W-BC sessions.

Temporal trends in semen concentration and count among 327 373 Chinese healthy men from 1981 to 2019: a systematic review.

STUDY QUESTION: Are there temporal trends of sperm concentration (SC) and total sperm count (TSC) in Chinese healthy males from 1981 to 2019? SUMMARY ANSWER: Our result indicated a temporal decrease in SC and TSC among 327 373 healthy Chinese men in the recent four decades. WHAT IS KNOWN ALREADY: A review of 61 papers reported a temporal decline in SC and TSC from 1938 to 1990. This trend was later confirmed by a systematic review of 185 published papers from 1981 to 2013. However, the majority of the included individuals were from western countries. In China, whether SC and TSC have declined remains controversial. STUDY DESIGN, SIZE, DURATION: This systematic review of published articles used data extracted from Pubmed, Science Direct, Embase, China-National-Knowledge-Infrastructure (CNKI) and Wanfang Data to assess changes in SC and TSC in China from 1981 to 2019. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 111 studies including 327 373 individuals who provided semen samples from 1981 to 2019 were extracted for the present analysis. Study selection and data extraction were performed by two independent researchers. The trends in SC and TSC were analysed using liner-regression and meta-regression before and after adjusting for potential covariates. Moreover, subgroups, categorised based on geographic region, fertility status or recruitment source, were also analysed. MAIN RESULTS AND THE ROLE OF CHANCE: SC declined significantly (slope liner-regression = -0.748 million/ml/year; P = 0.005; slope meta-regression = -0.824 million/ml/year; P < 0.001) between 1981 and 2019 in China. Trends for TSC was similar to that for SC (slope liner-regression = -2.073 million/year; P = 0.032; slope meta-regression = -2.188 million/year; P = 0.003). In subgroup meta-regression analyses, males with definite fertility had continuous declines in SC (slope northern group=-2.268, P = 0.009; slope southern group=-1.014, P = 0.009) and TSC (slope northern group=-9.675, P = 0.010; slope southern group=-3.215, P = 0.042). However, in the unselected group, where fertility status was unknown, the obvious downward trend in SC was only seen in males from Northern regions (slope = -0.836, P = 0.003). Another subgroup analysis demonstrated that obvious decreases in SC (slope = -1.432, P < 0.001) and TSC (slope=-4.315, P = 0.001) were only seen in volunteer groups but not in pre-pregnancy examination groups and other recruitment groups. The results changed minimally in multiple sensitivity analyses. LIMITATIONS, REASONS FOR CAUTION: The validity of the meta-analysis results was limited mainly by the quality of the included studies. Additionally, our study spanned many decades and the recommended criteria for some semen parameter assessments have significantly changed, which may bring about some unavoidable bias. Moreover, the data remain insufficient especially in some provinces of China. WIDER IMPLICATIONS OF THE FINDINGS: The present study is the first study to report significant decreases in SC and TSC in 327 373 healthy Chinese men between 1981 and 2019, indicating a serious reproductive health warning. Further studies on the causes of the declines are urgently needed. STUDY FUNDING/COMPETING INTEREST(S): D.Z. is supported by the National Natural Science Funding of China, Natural Science Funding of Shaanxi Province, Science Funding of Health Department, Shaanxi Province, Fundamental Research Funds for the Central University and the Project of Independent Innovative Experiment for Postgraduates in Medicine in Xi'an Jiaotong University. The authors have no conflicts of interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Emulsion Droplet Crystallinity Attenuates Postprandial Plasma Triacylglycerol Responses in Healthy Men: A Randomized Double-Blind Crossover Acute Meal Study.

BACKGROUND: The presence of triacylglycerol (TAG) cystallinity is assumed to influence digestibility and postprandial lipemia (PPL), although studies to date are limited. OBJECTIVE: This study aimed to investigate whether the presence of solid fat compared with undercooled liquid oil, specifically, plays a role in determining PPL by comparing emulsion droplets differing only in terms of physical state. METHODS: Ten percent palm stearin and 0.4% sorbitan monostearate emulsions were tempered to contain identically sized, charged, and shaped (spherical) undercooled liquid (LE) compared with partially crystalline solid (SE; mean ± SEM: 33.2% ± 0.03% solid fat at 37°C) droplets. Fifteen healthy fasting adult men (mean ± SD age: 27.5 ± 5.7 y; BMI: 24.1 ± 2.5 kg/m2) consumed 500 mL of each emulsion on separate occasions and plasma TAG concentrations, particle size of the plasma chylomicron-rich fraction (CMRF), and fatty acid (FA) composition of the CMRF-TAG were serially determined in a 6-h postprandial randomized double-blind crossover acute meal study. Changes from baseline values were analyzed by repeated-measures ANOVA. RESULTS: An earlier (2 compared with 3 h, P < 0.05) significant rise, a 39.9% higher mean postprandial TAG change from baseline (P = 0.08), and higher peak concentration (mean ± SEM: 1.47 ± 0.19 compared with 1.20 ± 0.15 mmol/L, P = 0.04) and iAUC (1.95 ± 0.39 compared with 1.45 ± 0.31 mmol/L × h, P = 0.03) values were observed for LE compared with SE. The compositions of the CMRF-TAG FAs shifted toward those of the ingested palm stearin by 4 h but did not differ between SE and LE (P = 0.90). Nor were there differences in postprandial changes in CMRF particle size (P = 0.79) or nonesterified FAs (P = 0.72) based on lipid physical state. CONCLUSIONS: Despite their identical compositions and colloidal properties, differences in lipid absorption were observed between SE and LE in healthy adult men. This is direct evidence that TAG physical state contributes to PPL, with the presence of solid fat having an attenuating influence.This trial was registered at clinicaltrials.gov as NCT03515590.

Reliability of manometry for assessing pelvic floor muscle function in healthy men.

OBJECTIVES: To the best of our knowledge, no study has examined the reliability of assessment methods for male pelvic floor muscle (PFM) function. Therefore, this study aimed to clarify the reliability of manometry with an anal sensor (Peritron cat 9300A) to assess PFM function in healthy men. METHODS: Healthy male subjects (n = 21) without urinary leakage underwent testing to assess PFM function, and intra- and interrater reliability tests among examiners were performed. The PFM function included maximal anorectal squeeze pressure, endurance, mean anorectal squeeze pressure, gradient, and area under the curve during PFM voluntary contraction. RESULTS: Participants had a median age of 38 years (range 26-51), and a mean BMI of 23.2 ± 2.0 kg/m2 . Satisfactory intra- and interrater reliability scores were found for resting pressure, anorectal squeeze pressure, and endurance. The intra-rater reliability of resting pressure, anorectal squeeze pressure, and endurance were 0.71, 0.89, and 0.75 for examiner 1 and 0.72, 0.89, and 0.87 for examiner 2. The interrater reliability for resting pressure, anorectal squeeze pressure, and endurance were 0.58, 0.93, and 0.61, respectively. CONCLUSIONS: This is the first prospective study showing the favorable intra- and interrater reliability of manometry for PFM function in healthy men. Our findings demonstrated that manometry can provide both reliable and reproducible data regarding PFM function in continent men, suggesting Peritron cat 9300A can be used to evaluate the PFM function in men.

[Indicators of protein, lipid, carbohydrate, purine metabolism and the level of pituitary hormones in healthy men of 22-55 years old.]

The levels of total protein, glucose, cholesterol and its fractions, triglycerides, uric acid, prolactin, thyroid-stimulating hormone (TSH), luteinizing hormone (LH), follicle-stimulating hormone (FSH), growth hormone in the serum, blood pressure (BP), calculated body mass index (BMI) were analyzed in 60 healthy men aged 22-55 years old. To assess the age dynamics of the parameters, groups of young (up to 35 years old) and middle age (over 35 years old) were formed according to the classification adopted at the International Symposium on Age Periodization in 1965. The correlation analysis of the parameters of the biochemical parameters, level pituitary hormones, age, BMI, level of mean blood pressure was made. There are a decrease (p<0,05) of total blood protein level (within the normal range), a tendency to a decrease in prolactin levels (PRL), an increase (p<0,05) of total cholesterol, LDL cholesterol in middle age group compared with the younger group. HDL cholesterol levels did not differ in the groups; this demonstrates the constancy of antiatherogenic protection over many decades. A slight decrease in total protein in the blood and a tendency to a decrease in the level of PRL with increasing age against the background of a negative correlations between the low degree of PRL and age (r=-0,20; p=0,01), total protein and age (r=-0,35; p=0,01) confirm the participation of PRL in protein metabolism, and also indirectly indicate changes in the regulatory effect of dopamine on prolactin synthesis and secretion.

Correlation between pelvic floor strength and physical activity level in healthy men.

The male pelvic floor muscles comprise a pair of compound muscle layers referred to as the levator ani. Studies have shown that pelvic floor muscle strength is affected by physical activity. This study aimed to assess male pelvic floor muscle strength through manometry of the external anal sphincter and evaluation of its association with physical activity level, BMI, and rectal pressure in healthy men. To assess physical activity level over the previous week, we used the International Physical Activity Questionnaire 8 (IPAQ). Pelvic floor muscle strength was assessed via anorectal manometry. The results shows a negative correlation between resting pressure and MET, a positive correlation between rectal pressure and resting and maximum pressure. The novel finding of this study is a negative correlation between walking and pelvic floor strength. This study raises new questions about the understanding of the interaction among physical activity, intraabdominal pressure, and pelvic floor strength in the physiology of continence in men.

Metabolic Profiling Reveals Differences in Plasma Concentrations of Arabinose and Xylose after Consumption of Fiber-Rich Pasta and Wheat Bread with Differential Rates of Systemic Appearance of Exogenous Glucose in Healthy Men.

BACKGROUND: The consumption of products rich in cereal fiber and with a low glycemic index is implicated in a lower risk of metabolic diseases. Previously, we showed that the consumption of fiber-rich pasta compared with bread resulted in a lower rate of appearance of exogenous glucose and a lower glucose clearance rate quantified with a dual-isotope technique, which was in accordance with a lower insulin and glucose-dependent insulinotropic polypeptide response. OBJECTIVE: To gain more insight into the acute metabolic consequences of the consumption of products resulting in differential glucose kinetics, postprandial metabolic profiles were determined. METHODS: In a crossover study, 9 healthy men [mean ± SEM age: 21 ± 0.5 y; mean ± SEM body mass index (kg/m2): 22 ± 0.5] consumed wheat bread (132 g) and fresh pasta (119 g uncooked) enriched with wheat bran (10%) meals. A total of 134 different metabolites in postprandial plasma samples (at -5, 30, 60, 90, 120, and 180 min) were quantified by using a gas chromatography-mass spectrometry-based metabolomics approach (secondary outcomes). Two-factor ANOVA and advanced multivariate statistical analysis (partial least squares) were applied to detect differences between both food products. RESULTS: Forty-two different postprandial metabolite profiles were identified, primarily representing pathways related to protein and energy metabolism, which were on average 8% and 7% lower after the men consumed pasta rather than bread, whereas concentrations of arabinose and xylose were 58% and 53% higher, respectively. Arabinose and xylose are derived from arabinoxylans, which are important components of wheat bran. The higher bioavailability of arabinose and xylose after pasta intake coincided with a lower rate of appearance of glucose and amino acids. We speculate that this higher bioavailability is due to higher degradation of arabinoxylans by small intestinal microbiota, facilitated by the higher viscosity of arabinoxylans after pasta intake than after bread intake. CONCLUSION: This study suggests that wheat bran, depending on the method of processing, can increase the viscosity of the meal bolus in the small intestine and interfere with macronutrient absorption in healthy men, thereby influencing postprandial glucose and insulin responses. This trial was registered at www.controlled-trials.com as ISRCTN42106325.

Differences of craniotype distribution and types of face among apparently healthy men from different regions of Ukraine.

Established peculiarities of craniotype distribution and types of face in somatically healthy men depend on regional affiliation. In all regions of Ukraine, markedly greater brachycephaly percentage was found, indicating the trend towards brachycephalisation and prevalence of men with narrow and very narrow face, which confirms gracilisation. The study showed a small number of regional differences in the distribution of specific types of the skull and face, indicating that the population of Ukraine is very homogeneous in anthropological composition and none of the presented Ukrainian regional types is beyond anthropological type, common to people in general.

Basal and insulin-regulated VLDL1 and VLDL2 kinetics in men with type 2 diabetes.

AIMS/HYPOTHESIS: Hypertriacylglycerolaemia is a hallmark of diabetic dyslipidaemia with increased concentrations of triacylglycerol (TG)-rich VLDL1 particles. However, whether VLDL1 secretion or removal is abnormal in type 2 diabetes remains unclear. The aim of this study was to compare basal and insulin-mediated VLDL1- and VLDL2-TG kinetics in men with type 2 diabetes and healthy men using a novel direct VLDL1- and VLDL2-TG labelling method. METHODS: Twelve men with type 2 diabetes and 12 healthy men matched for age and BMI were recruited. VLDL1- and VLDL2-TG turnover were measured during a 4 h basal period and a 3.5 h hyperinsulinaemic clamp period using a primed-constant infusion of ex vivo labelled VLDL1-TG and VLDL2-TG. RESULTS: Basal VLDL1-TG and VLDL2-TG secretion rates were similar in men with diabetes and healthy men. During hyperinsulinaemia, VLDL1-TG secretion rates were suppressed significantly in both groups, whereas no suppression of VLDL2-TG secretion rate was observed. VLDL1-TG to VLDL2-TG transfer rate was not significantly different from zero in both groups, while VLDL1-TG fatty acid oxidation rate was substantial, with a contribution to total energy expenditure of approximately 15% during postabsorptive conditions. VLDL1 and VLDL2 particle size (TG/apolipoprotein B [apoB] ratio) and apoB-100 concentration were unaltered by hyperinsulinaemia in men with type 2 diabetes, but significantly reduced in healthy men. CONCLUSIONS/INTERPRETATION: Insulin inhibits VLDL1-TG secretion rate similarly in age- and BMI-matched men with type 2 diabetes and healthy men, while VLDL2-TG secretion is unaltered by hyperinsulinaemia. However, VLDL1- and VLDL2-apoB levels are not lowered by hyperinsulinaemia in men with type 2 diabetes, which is indicative of a diminished hepatic response to insulin. TRIAL REGISTRATION: ClinicalTrials.gov NCT01564550.

Longer oral exposure with modified sham feeding does not slow down gastric emptying of low- and high-energy-dense gastric loads in healthy young men.

BACKGROUND: A long oral exposure to food and a high-energy density of food have been shown to increase satiety feelings. The effect of energy density is predominantly caused by an inhibition of gastric emptying. It is hypothesized that prolonging oral exposure may have an additional effect on this inhibition of gastric emptying. However, little human data are available to support this hypothesis. OBJECTIVE: The objective was to assess the effect of the duration of oral exposure to food on gastric emptying rate of gastric loads (GLs) low and high in energy density and on satiety feelings. METHODS: Twenty-six healthy men [mean ± SD age: 22 ± 3 y; BMI (in kg/m(2)): 23 ± 1] participated in a randomized crossover trial with 4 treatments and a control. Treatments consisted of either 1- or 8-min modified sham feeding (MSF) of cake, and a GL of either 100 or 700 kcal infused in the stomach via a nasogastric tube (500 mL, 62.5 mL/min). The control consisted of no MSF and a GL of 500 mL of water. Gastric emptying rate was assessed with a (13)C breath test. Breath samples and satiety feelings were collected at fixed time points until 90 min after start of the treatment. RESULTS: Gastric emptying rate and satiety feelings were not affected by duration of MSF (P ≥ 0.27). However, the 700-kcal GL treatments slowed gastric emptying [41% lower area under the curve (AUC)] and increased satiety feelings (22-31% higher AUC) compared with the 100-kcal GL treatments (P < 0.001). No interaction between MSF duration and energy density of GL was found (P ≥ 0.44). CONCLUSIONS: Higher gastric energy density inhibited gastric emptying and increased satiety feelings in healthy young men. However, prolonging oral exposure to food did not have an additional effect. This study provides more insight in satiety regulation. This trial was registered at trialregister.nl as NTR3601.

Trans fatty acid intake is inversely related to total sperm count in young healthy men.

STUDY QUESTION: Is intake of fatty acids related to semen quality among young men? SUMMARY ANSWER: The intake of trans fatty acids is inversely related to total sperm count in healthy young men. WHAT IS KNOWN ALREADY: Spain has seen an increase in the proportion of calories consumed as fat over the same period that a downward trend in semen quality has been observed. In addition, rodent models suggest that trans fat intake may severely affect testicular function. STUDY DESIGN, SIZE, DURATION: Cross-sectional study of 209 men recruited between October 2010 and November 2011. PARTICIPANTS/MATERIALS, SETTING, METHODS: A group of 209 healthy young university students 18-23 years of age provided a semen sample and completed a previously validated food frequency questionnaire. The association between intake of fatty acids with semen quality parameters (sperm concentration, motility, morphology and total count) was assessed using multivariate linear regression. MAIN RESULTS AND THE ROLE OF THE CHANCE: Trans fatty acid intake was inversely related to total sperm count after adjusting for potential confounders (P, trend = 0.03). The multivariate adjusted mean (95% confidence interval) total sperm count in increasing quartiles of trans fat intake was 144 (110-190), 113 (87-148), 100 (18-130) and 89 (69-117). There also was an inverse association between cholesterol intake and ejaculate volume (P, trend = 0.04). No other statistically significant relations were observed. LIMITATIONS, REASONS FOR CAUTION: The cross-sectional design of the study limits causal inference, we cannot exclude the possibility of unmeasured confounding and there was insufficient statistical power to identify modest associations. WIDER IMPLICATIONS OF THE FINDINGS: The results of this study, together with previous experimental work in rodents and biomarker studies among infertility patients, suggest that intake of trans fatty acids may be related to lower semen quality. Although the data provide further evidence that diet is a modifiable factor that could impact male fertility, it is not known whether the observed differences in sperm count translate into differences in fertility. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by The Seneca Foundation, Regional Agency of Science and Technology, grant no 00694/PI/04, Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (FIS), grant no PI10/00985, and grant P30 DK46200 from the National Institutes of Health. The authors have no competing interests to declare.

SHBG gene polymorphisms and their influence on serum SHBG, total and free testosterone concentrations in men.

CONTEXT: Genetic variation in sex hormone-binding globulin (SHBG) structure may affect estimates of sex steroid exposure by altering the affinity of the protein for its ligand. Consequently, free hormone calculations assuming constant binding affinity may, for certain genetic variations, lead to incorrect diagnoses if genetic variation is not taken into consideration. OBJECTIVE: To investigate the effects of genetic variation in SHBG on calculated and measured serum free testosterone (T) in men. DESIGN, SETTING AND PARTICIPANTS: Population-based sibling-pair study in 999 healthy men aged 25 to 45 (mean: 34.5) years. MAIN OUTCOME MEASURES: Genotyping using microarray (Illumina®) for SNPs suggested to affect binding affinity and/or concentration of SHBG or T. SHBG concentrations were measured using immunoassay and in a subset (n = 32) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Total T was measured using LC-MS/MS. Free T was calculated and in a subset (n = 314) measured directly using LC-MS/MS after equilibrium dialysis. RESULTS: Allelic frequencies of analyzed SNPs ranged from 0.5% to 58.2%. Compared to wild-type, SHBG concentrations were lower in rs6258 heterozygotes (-24.7%; p < 0.05) and higher in rs6259 heterozygotes, rs727428 homozygotes, and carriers of rs1799941 (+10.8 to 23.1%; all p < 0.05). Total T was higher in rs727428 homozygotes and carriers of rs5934505, rs1799941and rs6259 (+3.9 to 21.4%; all p < 0.05). No clear effects on measured free T were found, except for a trend towards higher values in rs6259 homozygotes, significant for calculated free T (+18.7%; p < 0.05) in the larger global study population. CONCLUSION: In these men, analyzed SNPs were relatively prevalent and affected serum concentrations of total T and SHBG but not calculated or measured free T except for a higher trend in rs6259 homozygotes.

A four-in-one first-in-human study to assess safety, tolerability, pharmacokinetics, pharmacodynamics, and concentration-QTc relationship of HRS-1780, a selective non-steroidal mineralocorticoid receptor antagonist, in healthy men.

BACKGROUND: This first-in-human study evaluated HRS-1780, an oral selective non-steroidal mineralocorticoid receptor antagonist, in healthy men. RESEARCH DESIGN AND METHODS: In single ascending dose (SAD) part, 10 participants for each dose cohort (5, 10, 20, 40, 60, and 80 mg) were randomized (8:2) to HRS-1780 or placebo. In multiple ascending dose part, 12 participants for each dose (10, 20, and 40 mg) were randomized (9:3) to HRS-1780 or placebo once daily for 7 days. The primary endpoint was safety and tolerability. RESULTS: HRS-1780 was well tolerated with all adverse events being mild. In the steady state, the median time to maximum concentration (Tmax) was 0.750 h and mean half-life was 1.76-1.96 h. High-fat/high-calorie meal prolonged Tmax but did not affect exposure. Multiple dosing of HRS-1780 at 40 mg showed a decreasing trend in systolic blood pressure compared with placebo. Changes in plasma aldosterone and norepinephrine with HRS-1780 were higher compared to placebo. Upper bounds of two-sided 90% confidence interval of placebo-adjusted change-from-baseline QTcF were below 10 msec at the maximum concentration in SAD. The trial had limited sample size and short study duration. CONCLUSIONS: HRS-1780 had favorable safety and pharmacokinetic profiles and did not cause clinically meaningful QTcF prolongation. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05638126).

Effects of Acute Beetroot Juice Supplementation and Exercise on Cardiovascular Function in Healthy Men in Preliminary Study: A Randomized, Double-Blinded, Placebo-Controlled, and Crossover Trial.

Nitrate-rich beetroot juice (NRBRJ) can potentially enhance exercise performance and improve cardiovascular function, leading to an increased use of NRBRJ over the years. However, the combined effects of NRBRJ supplementation and exercise on cardiovascular function remain unclear. Therefore, this study compared cardiovascular function responses to submaximal exercise with either placebo (PLA) or NRBRJ supplementation in healthy men. Twelve healthy men (aged 25.2 ± 2.3 years) completed the 30-min submaximal cycle ergometer exercise trials corresponding to 70% maximal heart rate (HRmax) with either PLA or NRBRJ supplementation in a random order. The mean exercise load, heart rate (HR), stroke volume (SV), cardiac output (CO), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and total peripheral resistance (TPR) were measured during exercise. The brachial-ankle pulse wave velocity (baPWV) and flow-mediated dilation (FMD) were measured before and after exercise. NRBRJ supplementation was more effective than PLA in increasing the mean exercise load and decreasing DBP and MAP during submaximal exercise. Furthermore, baPWV decreased in the NRBRJ trial and was considerably lower after exercise in the NRBRJ-supplemented group than in the PLA-supplemented group. FMD significantly increased in the PLA and NRBRJ trials; however, NRBRJ supplementation demonstrated a significantly higher FMD before and after exercise than PLA supplementation. In conclusion, acute NRBRJ supplementation and exercise were more effective than PLA supplementation and exercise in improving aerobic exercise capacity and cardiovascular function in healthy men.

Sex steroids and androgen biomarkers in the healthy man study: within-person variability and impact of fasting.

OBJECTIVE: Serum testosterone measurements in clinical practice mostly utilize "direct" (non-extraction) immunoassays which have method-specific bias due to steroid cross-reactivity and nonspecific matrix artifacts. Although more accurate, sensitive, and specific liquid chromatography-mass spectrometry (LCMS) dominates in clinical research, the within-person variability of serum testosterone in healthy men using LCMS measurement is not reported. DESIGN: Longitudinal multi-sampling observational study of men in excellent health over 3 months. METHODS: Elite healthy men (n = 325) over 40 years of age in excellent, asymptomatic health provided 9 blood samples over 3 months with serum testosterone, dihydrotestosterone (DHT), estradiol (E2), and estrone (E1) measured by validated LCMS with conventional biochemical and anthropometric variables. RESULTS: Quantitative estimates of within-person variability within day and between day, week, month, and quarter were stable other than an increase due to fasting. The androgen biomarkers most sensitive to age and testosterone among widely used biochemical and anthropometric variables in middle-aged and older men were identified. CONCLUSIONS: This study provides estimates of variability in serum testosterone and the best androgen biomarkers that may prove useful for future studies of androgen action in male ageing.

Seasonal Variation in Vitamin D Status Does Not Interfere with Improvements in Aerobic and Muscular Endurance in Conscripts during Basic Military Training.

Considering a lack of respective data, the primary objective of this study was to assess whether seasonal variation in vitamin D status (D-status) affects the extent of improvement in physical performance (PP) in conscripts during basic military training (BMT). D-status, PP and several blood parameters were measured repeatedly in conscripts whose 10-week BMT started in July (cohort S-C; n = 96) or in October (cohort A-C; n = 107). D-status during BMT was higher in S-C compared to A-C (overall serum 25(OH)D 61.4 ± 16.1 and 48.5 ± 20.7 nmol/L, respectively; p < 0.0001). Significant (p < 0.05) improvements in both aerobic and muscular endurance occurred in both cohorts during BMT. Pooled data of the two cohorts revealed a highly reliable (p = 0.000) but weak (R2 = 0.038-0.162) positive association between D-status and PP measures both at the beginning and end of BMT. However, further analysis showed that such a relationship occurred only in conscripts with insufficient or deficient D-status, but not in their vitamin D-sufficient companions. Significant (p < 0.05) increases in serum testosterone-to-cortisol ratio and decreases in ferritin levels occurred during BMT. In conclusion, a positive association exists between D-status and PP measures, but seasonal variation in D-status does not influence the extent of improvement in PP in conscripts during BMT.

Late, but Not Early, Night Sleep Loss Compromises Neuroendocrine Appetite Regulation and the Desire for Food.

OBJECTIVE: There is evidence that reduced sleep duration increases hunger, appetite, and food intake, leading to metabolic diseases, such as type 2 diabetes and obesity. However, the impact of sleep timing, irrespective of its duration and on the regulation of hunger and appetite, is less clear. We aimed to evaluate the impact of sleep loss during the late vs. early part of the night on the regulation of hunger, appetite, and desire for food. METHODS: Fifteen normal-weight ([mean ± SEM] body-mass index: 23.3 ± 0.4 kg/m2) healthy men were studied in a randomized, balanced, crossover design, including two conditions of sleep loss, i.e., 4 h sleep during the first night-half ('late-night sleep loss'), 4 h sleep during the second night-half ('early-night sleep loss'), and a control condition with 8h sleep ('regular sleep'), respectively. Feelings of hunger and appetite were assessed through visual analogue scales, and plasma ghrelin and leptin were measured from blood samples taken before, during, and after night-time sleep. RESULTS: Ghrelin and feelings of hunger and appetite, as well as the desire for food, were increased after 'late-night sleep loss', but not 'early-night sleep loss', whereas leptin remained unaffected by the timing of sleep loss. CONCLUSIONS: Our data indicate that timing of sleep restriction modulates the effects of acute sleep loss on ghrelin and appetite regulation in healthy men. 'Late-night sleep loss' might be a risk factor for metabolic diseases, such as obesity and type 2 diabetes. Thereby, our findings highlight the metabolic relevance of chronobiological sleep timing.

Serum and Urine Metabolites in Healthy Men after Consumption of Acidified Milk and Yogurt.

The identification of molecular biomarkers that can be used to quantitatively link dietary intake to phenotypic traits in humans is a key theme in modern nutritional research. Although dairy products (with and without fermentation) represent a major food group, the identification of markers of their intake lags behind that of other food groups. Here, we report the results from an analysis of the metabolites in postprandial serum and urine samples from a randomized crossover study with 14 healthy men who ingested acidified milk, yogurt, and a non-dairy meal. Our study confirms the potential of lactose and its metabolites as markers of lactose-containing dairy foods and the dependence of their combined profiles on the fermentation status of the consumed products. Furthermore, indole-3-lactic acid and 3-phenyllactic acid are two products of fermentation whose postprandial behaviour strongly discriminates yogurt from milk intake. Our study also provides evidence of the ability of milk fermentation to increase the acute delivery of free amino acids to humans. Notably, 3,5-dimethyloctan-2-one also proves to be a specific marker for milk and yogurt consumption, as well as for cheese consumption (previously published data). These molecules deserve future characterisation in human interventional and observational studies.