human
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Cross-sectional studies indicate a positive relation between serum 25-hydroxyvitamin D [ 25(OH)D ] and testosterone . It is not known if this relation is causal , which in theory could be in both directions . A cross-sectional population based study was design ed with pooled data from 3 vitamin D r and omized clinical trials ( RCTs ) performed in Tromsø with weight reduction , insulin sensitivity , and depression scores as endpoints , and one  testosterone RCT in subjects with low serum testosterone ( < 11.0 nmol/l ) and with body composition as endpoint .  Serum 25(OH)D and and rogens were measured in 893 males in the cross-sectional part , at baseline and after 6 - 12 months of supplementation with vitamin D 20 000 IU-40 000 IU per week vs. placebo in the vitamin D RCTs ( n=282 ) , and at baseline and after one year treatment with testosterone undecanoate 1 000 mg or placebo injections ( at baseline and after 6 , 16 , 28 , and 40 weeks ) in the testosterone RCT ( n=37 ) . In the cross-sectional study , serum 25(OH)D was found to be a significant and positive predictor of serum testosterone . In the vitamin D RCTs , no significant effect on serum total or free testosterone levels was seen , and in the testosterone RCT no significant effect on serum 25(OH)D was seen . This was unchanged in sub-analyses in subjects with low serum 25(OH)D ( or testosterone ) levels . In conclusion , in subjects without significant vitamin D deficiency , there is no increase in serum testosterone after high dose vitamin D supplementation . Similarly , in subjects with moderately low serum testosterone levels  , substitution with testosterone does not increase serum Vascular endothelial growth factor ( VEGF ) has been suggested to play a role in the pathophysiology of polycystic ovary syndrome ( PCOS ) and may contribute to increased risk of ovarian hyperstimulation syndrome ( OHSS ) in affected individuals .  Vitamin D ( VitD ) supplementation improves multiple clinical parameters in VitD-deficient women with PCOS and decreases VEGF levels in several other pathologic conditions . Unveiling the basic mechanisms underlying the beneficial effects of vitamin D on PCOS may enhance our underst and ing of the pathophysiology of this syndrome . It may also suggest a new treatment for PCOS that can improve it through the same mechanism as vitamin D and can be given regardless of vitamin D levels . Therefore , we aim ed to explore the effect of VitD supplementation on serum VEGF levels and assess whether changes in VEGF correlate with an improvement in characteristic clinical abnormalities of PCOS . This is a r and omized placebo-controlled trial conducted between October 2013 and March 2015 . Sixty-eight VitD-deficient women with PCOS were recruited . Women received either 50,000 IU of oral VitD3 or placebo once weekly for 8 weeks . There was a significant decrease in serum VEGF levels ( 1106.4 ± 36.5 to 965.3 ± 42.7 pg·mL–1 ; p < 0.001 ) in the VitD group . Previously reported findings of this trial demonstrated a significant decrease in the intermenstrual intervals , Ferriman-Gallwey hirsutism score , and triglycerides  following VitD supplementation . Interestingly , ∆VEGF was positively correlated with ∆triglycerides ( R2 = 0.22 ; p = 0.02 ) following VitD supplementation . In conclusion , VitD replacement significantly decreases serum VEGF levels correlating with a decrease in triglycerides in women with PCOS . This is a novel molecular explanation for the beneficial effects of VitD treatment . It also suggests the need to investigate a potential role of VitD treatment in reducing the incidence or severity of OHSS in VitD-deficient women with PCOS Background — The relation between endogenous testosterone concentrations and health in men is controversial . Methods and Results — We examined the prospect i ve relationship between endogenous testosterone concentrations and mortality due to all causes , cardiovascular disease , and cancer in a nested case-control study based on 11 606 men aged 40 to 79 years surveyed in 1993 to 1997 and followed up to 2003 . Among those without prevalent cancer or cardiovascular disease , 825 men who subsequently died were compared with a control group of 1489 men still alive , matched for age and date of baseline visit .  Endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes ( 825 deaths ) , cardiovascular disease ( 369 deaths ) , and cancer ( 304 deaths ) . Odds ratios ( 95 % confidence intervals ) for mortality for increasing quartiles of endogenous testosterone compared with the lowest quartile were 0.75 ( 0.55 to 1.00 ) , 0.62 ( 0.45 to 0.84 ) , and 0.59 ( 0.42 to 0.85 ) , respectively ( P<0.001 for trend after adjustment for age , date of visit , body mass index , systolic blood pressure , blood cholesterol , cigarette smoking , diabetes mellitus , alcohol intake , physical activity , social class , education , dehydroepi and rosterone sulfate , and rostanediol glucuronide , and sex hormone binding globulin ) . An increase of 6 nmol/L serum testosterone ( ≈1 SD ) was associated with a 0.81 ( 95 % confidence interval 0.71 to 0.92 , P<0.01 ) multivariable-adjusted odds ratio for mortality . Inverse relationships were also observed for deaths due to cardiovascular causes and cancer and after the exclusion of deaths that occurred in the first 2 years . Conclusions — In men  , endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes . Low testosterone may be a predictive marker for those at high risk of cardiovascular disease Context : Available evidence shows an association of vitamin D with and rogen levels in men . However , results from preliminary r and omized controlled trials ( RCTs ) are conflicting . Objective : To evaluate whether vitamin D supplementation increases total testosterone ( TT ) levels in healthy men . Design : The Graz Vitamin D&TT‐ RCT is a single‐center , double‐blind , r and omized , placebo‐controlled trial conducted between December 2012 and January 2017 . Setting : Endocrine outpatient clinic at the Medical University of Graz , Austria . Participants : Ninety‐eight healthy men with TT levels ≥10.4 nmol/L and 25‐hydroxyvitamin D [ 25(OH)D ] levels < 75 nmol/L completed the study . Intervention : Subjects were r and omly assigned to receive 20,000 IU/wk of vitamin D3 ( n = 50 ) or placebo ( n = 50 ) for 12 weeks . Main Outcome Measures : Primary outcome was TT measured using mass spectrometry . Secondary outcomes were free testosterone , sex hormone‐binding globulin , estradiol , follicle‐stimulating hormone , and luteinizing hormone levels ; free and rogen index ; metabolic characteristics ; and body composition . Results : In healthy men [ mean values ± st and ard deviation : age , 39 years ( ±13 years ) ; 25(OH)D level , 53.3 nmol/L ( ±18.3 nmol/L ) ; TT , 19.1 nmol/L ( ±5.6 nmol/l ) ] , no significant treatment effect on TT was found ; however , there were significant effects on quantitative insulin sensitivity check index ( QUICKI ) and a trend toward decreased Matsuda index . In the treatment group , median ( interquartile range ) changes for TT , QUICKI , and Matsuda index were 0.5 nmol/L ( −0.63 to 0.63 nmol/L ; P = 0.497 ) , −0.02 ( −0.04 to 0.01 ; P = 0.034 ) , and −0.9 ( −3.2 to 0.8 ; P = 0.051 ) , respectively . Conclusion : Vitamin D treatment had no effect on TT levels in middle‐aged healthy men with normal baseline TT , but it significantly decreased QUICKI . Additional studies investigating vitamin D effects on TT and insulin sensitivity in healthy men are required STUDY QUESTION Are low vitamin D levels linked with semen quality and sex steroids in infertile men ? SUMMARY ANSWER Infertile men with vitamin D deficiency had lower sperm motility , total numbers of motile sperm , Inhibin B , sex-hormone-binding-globulin ( SHBG ) and testosterone/estradiol ratio , but higher levels of free sex steroids , than infertile men with normal vitamin D levels . WHAT IS KNOWN ALREADY Low vitamin D levels have been associated with decreased sperm motility in healthy men , but a relationship between vitamin D and calcium with semen quality and especially sex steroids has not been sufficiently described in infertile men . STUDY DESIGN , SIZE , DURATION This study comprises baseline characteristics of 1427 infertile men screened from 2011 to 2014 for inclusion in a r and omized clinical trial , the Copenhagen-Bone-Gonadal Study . PARTICIPANTS / MATERIAL S , SETTING , METHODS In total 1427 infertile men , consecutively referred to our tertiary and rological centre for fertility workup , underwent a physical examination and had semen quality assessed based on two sample s and blood analysed for serum testosterone , SHBG , estradiol , inhibin B , luteinizing hormone , follicle-stimulating hormone ( FSH ) , 25-hydroxyvitamin D ( 25-OHD ) , ionized calcium ( Ca(2 + ) ) and karyotype . There were 179 men excluded due to serious comorbidities or anabolic steroid usage , leaving 1248 patients for analyses . MAIN RESULTS AND THE ROLE OF CHANCE Men with 25-OHD > 75 nmol/l had higher sperm motility and 66 and 111 % higher total numbers of motile spermatozoa after 45 and 262 min , respectively , than men with 25-OHD < 25 nmol/l ( all P < 0.05 ) . SHBG levels and testosterone/estradiol ratios were 15 and 14 % lower , respectively , while free testosterone and estradiol ratios were 6 and 13 % higher , respectively , in men with 25-OHD < 25 nmol/l ( all P < 0.05 ) . Men with lower Ca(2 + ) levels had higher progressive sperm motility and inhibin B/FSH ratio but lower testosterone/estradiol ratio ( all P < 0.05 ) . LIMITATIONS , REASONS FOR CAUTION All outcomes presented are predefined end-points but inferral of causality is compromised by the descriptive study design . It remains to be shown whether the links between vitamin D , calcium , semen quality and sex steroids in infertile men are causal . WIDER IMPLICATION S OF THE FINDINGS The associations between vitamin D deficiency and low calcium with semen quality and sex steroids support the existence of a cross-link between regulators of calcium homeostasis and gonadal function in infertile men . STUDY FUNDING /COMPETING INTERESTS This study was supported by the Danish Agency for Science , Technology and Innovation , Hørslev Fonden , Danish Cancer Society and Novo Nordisk Foundation . There are no conflicts of interest . TRIAL REGISTRATION NUMBER NCT01304927 . DATE OF TRIAL REGISTRATION 25 February 2011 . DATE OF ENROLMENT OF FIRST PATIENT 8 March 2011 BACKGROUND Obese adolescents are at a greater risk of vitamin D deficiency because vitamin D is thought to be sequestered by excess adipose tissue . Poor vitamin D status has been associated with a higher prevalence of the metabolic syndrome , type 2 diabetes , or both in adults and adolescents . OBJECTIVE The objective was to determine in obese adolescents the efficacy and safety of 4000 IU vitamin D3/d and whether subsequent increased circulating concentrations of 25-hydroxyvitamin D [ 25(OH)D ] are associated with improved markers of insulin sensitivity and resistance and reduced inflammation . DESIGN Obese adolescent patients [ n = 35 ; mean ± SD age : 14.1 ± 2.8 y ; BMI ( in kg/m(2 ) ) : 39.8 ± 6.1 ; 25(OH)D : 19.6 ± 7.1 ng/mL ] were recruited from the University of Missouri Adolescent Diabetes and Obesity Clinic and were r and omly assigned to receive either vitamin D3 ( 4000 IU/d ) or placebo as part of their st and ard care . 
    Output:
    
agent
***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Cross-sectional studies indicate a positive relation between serum 25-hydroxyvitamin D [ 25(OH)D ] and testosterone . It is not known if this relation is causal , which in theory could be in both directions . A cross-sectional population based study was design ed with pooled data from 3 vitamin D r and omized clinical trials ( RCTs ) performed in Tromsø with weight reduction , insulin sensitivity , and depression scores as endpoints , and one  testosterone RCT in subjects with low serum testosterone ( < 11.0 nmol/l ) and with body composition as endpoint .  Serum 25(OH)D and and rogens were measured in 893 males in the cross-sectional part , at baseline and after 6 - 12 months of supplementation with vitamin D 20 000 IU-40 000 IU per week vs. placebo in the vitamin D RCTs ( n=282 ) , and at baseline and after one year treatment with testosterone undecanoate 1 000 mg or placebo injections ( at baseline and after 6 , 16 , 28 , and 40 weeks ) in the testosterone RCT ( n=37 ) . In the cross-sectional study , serum 25(OH)D was found to be a significant and positive predictor of serum testosterone . In the vitamin D RCTs , no significant effect on serum total or free testosterone levels was seen , and in the testosterone RCT no significant effect on serum 25(OH)D was seen . This was unchanged in sub-analyses in subjects with low serum 25(OH)D ( or testosterone ) levels . In conclusion , in subjects without significant vitamin D deficiency , there is no increase in serum testosterone after high dose vitamin D supplementation . Similarly , in subjects with moderately low serum testosterone levels  , substitution with testosterone does not increase serum Vascular endothelial growth factor ( VEGF ) has been suggested to play a role in the pathophysiology of polycystic ovary syndrome ( PCOS ) and may contribute to increased risk of ovarian hyperstimulation syndrome ( OHSS ) in affected individuals .  Vitamin D ( VitD ) supplementation improves multiple clinical parameters in VitD-deficient women with PCOS and decreases VEGF levels in several other pathologic conditions . Unveiling the basic mechanisms underlying the beneficial effects of vitamin D on PCOS may enhance our underst and ing of the pathophysiology of this syndrome . It may also suggest a new treatment for PCOS that can improve it through the same mechanism as vitamin D and can be given regardless of vitamin D levels . Therefore , we aim ed to explore the effect of VitD supplementation on serum VEGF levels and assess whether changes in VEGF correlate with an improvement in characteristic clinical abnormalities of PCOS . This is a r and omized placebo-controlled trial conducted between October 2013 and March 2015 . Sixty-eight VitD-deficient women with PCOS were recruited . Women received either 50,000 IU of oral VitD3 or placebo once weekly for 8 weeks . There was a significant decrease in serum VEGF levels ( 1106.4 ± 36.5 to 965.3 ± 42.7 pg·mL–1 ; p < 0.001 ) in the VitD group . Previously reported findings of this trial demonstrated a significant decrease in the intermenstrual intervals , Ferriman-Gallwey hirsutism score , and triglycerides  following VitD supplementation . Interestingly , ∆VEGF was positively correlated with ∆triglycerides ( R2 = 0.22 ; p = 0.02 ) following VitD supplementation . In conclusion , VitD replacement significantly decreases serum VEGF levels correlating with a decrease in triglycerides in women with PCOS . This is a novel molecular explanation for the beneficial effects of VitD treatment . It also suggests the need to investigate a potential role of VitD treatment in reducing the incidence or severity of OHSS in VitD-deficient women with PCOS Background — The relation between endogenous testosterone concentrations and health in men is controversial . Methods and Results — We examined the prospect i ve relationship between endogenous testosterone concentrations and mortality due to all causes , cardiovascular disease , and cancer in a nested case-control study based on 11 606 men aged 40 to 79 years surveyed in 1993 to 1997 and followed up to 2003 . Among those without prevalent cancer or cardiovascular disease , 825 men who subsequently died were compared with a control group of 1489 men still alive , matched for age and date of baseline visit .  Endogenous testosterone concentrations at baseline were inversely related to mortality due to all causes ( 825 deaths ) , cardiovascular disease ( 369 deaths ) , and cancer ( 304 deaths ) . Odds ratios ( 95 % confidence intervals ) for mortality for increasing quartiles of endogenous testosterone compared with the lowest quartile were 0.75 ( 0.55 to 1.00 ) , 0.62 ( 0.45 to 0.84 ) , and 0.59 ( 0.42 to 0.85 ) , respectively ( P<0.001 for trend after adjustment for age , date of visit , body mass index , systolic blood pressure , blood cholesterol , cigarette smoking , diabetes mellitus , alcohol intake , physical activity , social class , education , dehydroepi and rosterone sulfate , and rostanediol glucuronide , and sex hormone binding globulin ) . An increase of 6 nmol/L serum testosterone ( ≈1 SD ) was associated with a 0.81 ( 95 % confidence interval 0.71 to 0.92 , P<0.01 ) multivariable-adjusted odds ratio for mortality . Inverse relationships were also observed for deaths due to cardiovascular causes and cancer and after the exclusion of deaths that occurred in the first 2 years . Conclusions — In men  , endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes . Low testosterone may be a predictive marker for those at high risk of cardiovascular disease Context : Available evidence shows an association of vitamin D with and rogen levels in men . However , results from preliminary r and omized controlled trials ( RCTs ) are conflicting . Objective : To evaluate whether vitamin D supplementation increases total testosterone ( TT ) levels in healthy men . Design : The Graz Vitamin D&TT‐ RCT is a single‐center , double‐blind , r and omized , placebo‐controlled trial conducted between December 2012 and January 2017 . Setting : Endocrine outpatient clinic at the Medical University of Graz , Austria . Participants : Ninety‐eight healthy men with TT levels ≥10.4 nmol/L and 25‐hydroxyvitamin D [ 25(OH)D ] levels < 75 nmol/L completed the study . Intervention : Subjects were r and omly assigned to receive 20,000 IU/wk of vitamin D3 ( n = 50 ) or placebo ( n = 50 ) for 12 weeks . Main Outcome Measures : Primary outcome was TT measured using mass spectrometry . Secondary outcomes were free testosterone , sex hormone‐binding globulin , estradiol , follicle‐stimulating hormone , and luteinizing hormone levels ; free and rogen index ; metabolic characteristics ; and body composition . Results : In healthy men [ mean values ± st and ard deviation : age , 39 years ( ±13 years ) ; 25(OH)D level , 53.3 nmol/L ( ±18.3 nmol/L ) ; TT , 19.1 nmol/L ( ±5.6 nmol/l ) ] , no significant treatment effect on TT was found ; however , there were significant effects on quantitative insulin sensitivity check index ( QUICKI ) and a trend toward decreased Matsuda index . In the treatment group , median ( interquartile range ) changes for TT , QUICKI , and Matsuda index were 0.5 nmol/L ( −0.63 to 0.63 nmol/L ; P = 0.497 ) , −0.02 ( −0.04 to 0.01 ; P = 0.034 ) , and −0.9 ( −3.2 to 0.8 ; P = 0.051 ) , respectively . Conclusion : Vitamin D treatment had no effect on TT levels in middle‐aged healthy men with normal baseline TT , but it significantly decreased QUICKI . Additional studies investigating vitamin D effects on TT and insulin sensitivity in healthy men are required STUDY QUESTION Are low vitamin D levels linked with semen quality and sex steroids in infertile men ? SUMMARY ANSWER Infertile men with vitamin D deficiency had lower sperm motility , total numbers of motile sperm , Inhibin B , sex-hormone-binding-globulin ( SHBG ) and testosterone/estradiol ratio , but higher levels of free sex steroids , than infertile men with normal vitamin D levels . WHAT IS KNOWN ALREADY Low vitamin D levels have been associated with decreased sperm motility in healthy men , but a relationship between vitamin D and calcium with semen quality and especially sex steroids has not been sufficiently described in infertile men . STUDY DESIGN , SIZE , DURATION This study comprises baseline characteristics of 1427 infertile men screened from 2011 to 2014 for inclusion in a r and omized clinical trial , the Copenhagen-Bone-Gonadal Study . PARTICIPANTS / MATERIAL S , SETTING , METHODS In total 1427 infertile men , consecutively referred to our tertiary and rological centre for fertility workup , underwent a physical examination and had semen quality assessed based on two sample s and blood analysed for serum testosterone , SHBG , estradiol , inhibin B , luteinizing hormone , follicle-stimulating hormone ( FSH ) , 25-hydroxyvitamin D ( 25-OHD ) , ionized calcium ( Ca(2 + ) ) and karyotype . There were 179 men excluded due to serious comorbidities or anabolic steroid usage , leaving 1248 patients for analyses . MAIN RESULTS AND THE ROLE OF CHANCE Men with 25-OHD > 75 nmol/l had higher sperm motility and 66 and 111 % higher total numbers of motile spermatozoa after 45 and 262 min , respectively , than men with 25-OHD < 25 nmol/l ( all P < 0.05 ) . SHBG levels and testosterone/estradiol ratios were 15 and 14 % lower , respectively , while free testosterone and estradiol ratios were 6 and 13 % higher , respectively , in men with 25-OHD < 25 nmol/l ( all P < 0.05 ) . Men with lower Ca(2 + ) levels had higher progressive sperm motility and inhibin B/FSH ratio but lower testosterone/estradiol ratio ( all P < 0.05 ) . LIMITATIONS , REASONS FOR CAUTION All outcomes presented are predefined end-points but inferral of causality is compromised by the descriptive study design . It remains to be shown whether the links between vitamin D , calcium , semen quality and sex steroids in infertile men are causal . WIDER IMPLICATION S OF THE FINDINGS The associations between vitamin D deficiency and low calcium with semen quality and sex steroids support the existence of a cross-link between regulators of calcium homeostasis and gonadal function in infertile men . STUDY FUNDING /COMPETING INTERESTS This study was supported by the Danish Agency for Science , Technology and Innovation , Hørslev Fonden , Danish Cancer Society and Novo Nordisk Foundation . There are no conflicts of interest . TRIAL REGISTRATION NUMBER NCT01304927 . DATE OF TRIAL REGISTRATION 25 February 2011 . DATE OF ENROLMENT OF FIRST PATIENT 8 March 2011 BACKGROUND Obese adolescents are at a greater risk of vitamin D deficiency because vitamin D is thought to be sequestered by excess adipose tissue . Poor vitamin D status has been associated with a higher prevalence of the metabolic syndrome , type 2 diabetes , or both in adults and adolescents . OBJECTIVE The objective was to determine in obese adolescents the efficacy and safety of 4000 IU vitamin D3/d and whether subsequent increased circulating concentrations of 25-hydroxyvitamin D [ 25(OH)D ] are associated with improved markers of insulin sensitivity and resistance and reduced inflammation . DESIGN Obese adolescent patients [ n = 35 ; mean ± SD age : 14.1 ± 2.8 y ; BMI ( in kg/m(2 ) ) : 39.8 ± 6.1 ; 25(OH)D : 19.6 ± 7.1 ng/mL ] were recruited from the University of Missouri Adolescent Diabetes and Obesity Clinic and were r and omly assigned to receive either vitamin D3 ( 4000 IU/d ) or placebo as part of their st and ard care . 
    Output:
    