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Phosphorus as predictive factor for erectile dysfunction in middle aged men: A cross sectional study in Korea

Authors:
  • National Police Hospital, Seoul, Korea

Abstract

Purpose High serum inorganic phosphorus level is related with atherosclerosis and an elevated risk of cardiovascular disease. At the same time, the association of phosphorus with erectile dysfunction (ED) is not well reported. We studied the effect of serum phosphorus on ED and the relationship with other clinical variables. Materials and Methods From March to September 2013, 1,899 police men aged 40 to 59 years who entered in a prostate health screening were targeted. All subjects underwent a clinical checking using the International Index of Erectile Function-5 (IIEF-5) questionnaire translated into Korean. Serum prostate-specific antigen (PSA), testosterone, inorganic phosphorus, body mass index, metabolic syndrome (MetS), and prostate ultrasound were also examined. Results Serum inorganic phosphorus (r=–0.108, p<0.001) had the highest correlation coefficient with IIEF-5 score other than age, followed by prostate volume (PV) (r=–0.065, P<0.001). Using logistic regression analysis, age, phosphorus, and MetS were predictive factors for moderate to severe ED in univariate analysis. PSA, testosterone, body mass index, and PV could not predict ED. Age, MetS, and phosphorus were independent predictive factors of moderate to severe ED (p<0.001; odds ratio [OR], 1.119; 95% confidence interval [CI] 1.086–1.153; p=0.048; OR, 1.283; 95% CI, 1.003–1.641; and p=0.048; OR, 1.101; 95% CI, 1.076–1.131) in the multivariate analysis. Conclusions In our study, phosphorus level is related with ED. Phosphorus is a significant predictor of ED and a strong factor that can be modified in the middle-age. Controlling phosphorus in men may have a particular meaning of preventing the occurrence of ED.
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INTRODUCTION
Phosphorus is necessary for several, various biological
roles in the signal transduction of cells and energy exchange
of human body. About 80%–90% of phosphorus is founded in
Phosphorus as predictive factor for erectile
dysfunction in middle aged men: A cross sectional
study in Korea
Seung Ki Min1, Kwibok Choi1, Soon Ki Kim1, Gyeong In Lee2, In-Chang Cho1
Departments of 1Urology and 2Laboratory Medicine, National Police Hospital, Seoul, Korea
Purpose: High serum inorganic phosphorus level is related with atherosclerosis and an elevated risk of cardiovascular disease. At
the same time, the association of phosphorus with erectile dysfunction (ED) is not well reported. We studied the effect of serum
phosphorus on ED and the relationship with other clinical variables.
Materials and Methods: From March to September 2013, 1,899 police men aged 40 to 59 years who entered in a prostate health
screening were targeted. All subjects underwent a clinical checking using the International Index of Erectile Function-5 (IIEF-5)
questionnaire translated into Korean. Serum prostate-specific antigen (PSA), testosterone, inorganic phosphorus, body mass index,
metabolic syndrome (MetS), and prostate ultrasound were also examined.
Results: Serum inorganic phosphorus (r=–0.108, p<0.001) had the highest correlation coefficient with IIEF-5 score other than age,
followed by prostate volume (PV) (r=–0.065, P<0.001). Using logistic regression analysis, age, phosphorus, and MetS were pre-
dictive factors for moderate to severe ED in univariate analysis. PSA, testosterone, body mass index, and PV could not predict ED.
Age, MetS, and phosphorus were independent predictive factors of moderate to severe ED (p<0.001; odds ratio [OR], 1.119; 95%
confidence interval [CI] 1.086–1.153; p=0.048; OR, 1.283; 95% CI, 1.003–1.641; and p=0.048; OR, 1.101; 95% CI, 1.076–1.131) in the
multivariate analysis.
Conclusions: In our study, phosphorus level is related with ED. Phosphorus is a significant predictor of ED and a strong factor that
can be modified in the middle-age. Controlling phosphorus in men may have a particular meaning of preventing the occurrence of
ED.
Keywords: Erectile dysfunction; Men; Middle aged; Phosphorus
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted
non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Original Article - Sexual Dysfunction/Infertility
Received: 13 September, 2016 Accepted: 17 October, 2016
Corresponding Author: In-Chang Cho
Department of Urology, National Police Hospital, 123 Songi-ro, Songpa-gu, Seoul 05715, Korea
TEL: +82-2-3400-1205, FAX: +82-2-431-3192, E-mail: uroiccho@gmail.com
The Korean Urological Association, 2016
teeth and bones. Mineral balance is regulated by a complex
interaction between gastrointestinal absorption, renal
excretion and translocation between parts of the human
body. The latter process is important during the f ast changes
of metabolism [1,2]. Impaired intestinal phosphate absorption,
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Investig Clin Urol 2016;57:442-448.
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pISSN 2466-0493 • eISSN 2466-054X
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Phosphorus and erectile dysfunction
renal phosphate reabsorption, and phosphate metabolism
can elevate serum phosphorus level [3]. Elevated serum
phosphorus is suspected to elevate the risk of cardiovascular
disease (CVD) through vascular calcif ication, myocardial
f ibrosis, and development of left ventricular hypertrophy [4-6].
Erectile dysfunction (ED) is a frequent problem that
affects about 15% of men 40 to 50 years of age, 45% of men
in their 60s, and 70% of men older than 70 [7]. In addition
to being a distressing condition itself, ED is thought to be a
harbinger of CVD and mortality. Organic ED and coronary
artery disease (CAD) are closely related, as endothelial
dysf unction leads to a restriction of blood f low [8,9]. ED
and CVD share many common risk f actors, such as age,
hypertension, insulin resistance, increased body mass index
(BMI), cholesterol, lower levels of high-density lipoprotein,
and smoking [10-14]. Overall atherosclerotic processes af f ect
arterial blood f low and lead to major pathophysiologic
changes that contribute to both cardiovascular and
peripheral vascular diseases, including ED [15]. There is a
growing body of evidence that ED is a sentinel marker of
subclinical CVD and likely precedes symptomatic CAD.
In light of these observations, we assessed whether
serum phosphorus is associated with erectile f unction in
middle-aged Korean men.
MATERIALS AND METHODS
1. Subjects
The proposal of our research was approved by the
Institutional Review Board of National Police Hospital
(No. 11100176-201608-HR-005). It is a cross-sectional study
including 1,899 male police of f icers ranging f rom 40 to 59
years who entered in a prostate health screening between
March and September 2013 at National Police Hospital.
People who were taking drugs affecting prostate physiology,
such as antiandrogens and 5-α-reductase inhibitors, who
used phosphodiesterase-5 inhibitors daily or nutrients that
might adjust mineral or bone metabolism, who had palpable
nodules on the digital rectal examination, or who showed a
high prostate-specif ic antigen (PSA) level (>4.0 ng/mL) were
not included in our study. Additionally, patients diagnosed
with chronic kidney disease were excluded.
2. Questionnaire and blood samples including
phosphorus measurement
All subjects underwent a clinical checking using the
IIEF-5 questionnaire translated into Korean. Blood samples
were obtained to measure serum PSA, testosterone, and
phosphorus between 7:00 AM an d 9:00 AM after eight
hours f asting. Total PSA was measured by an ABBOTT
ARCHITECT i2000 analyzer using the Abbott ARCHITECT
Total PSA assay ( Abbott Laboratories, Slingo, Ireland).
Serum testosterone was calculated by RIA (Parc Marcel
Boiteux, Codolet, Cisbio Bioassays Inc., Codolet, France).
Serum inorganic phosphorus was determined with a Hitachi
7600-020 (Hitachi Co., Tokyo, Japan) autoanalyzer using
HRII Series P-HRII reagent (Wako Pure Cemical Industries
Ltd, Osaka, Japan ).
3. BPH assessment
Certif ied version of the IPSS was served to participants
to evaluate voiding symptoms. Prostate volume (PV) was
measured by transrectal ultrasound (UltraV iew, BK medical,
Copenhagen, Denmark), and digital rectal examination of
prostate was also carried out.
4. Metabolic syndrome assessment
Blood pressure was measured over twice (5 minutes
apart) in the right arm using a digital blood pressure
monitors, were averaged. Waist circumference was measured
at the level of uppermost border of hipbones (iliac crest).
Records of height and body weight were also collected. Blood
was sampled at the same time of day (7:00–9:00 AM) in the 8
hours f asting state. Chemistry tests included measurements
of serum glucose, total cholesterol, high-density lipoprotein
cholesterol, low-density lipoprotein cholesterol, and
triglycerides. Metabolic syndrome (MetS) was diagnosed in
case of three or more of the National Cholesterol Education
Program Adult Treatment Panel III for Asians criteria were
c o nf i r m ed [ 16 ].
5. Statistical analysis
First, one-way analysis of variance tests were assessed
to compare the differences in IIEF-5 scores according to
other factors, such as age, BMI, testosterone level, PSA,
phosphorus, and PV. Chi-square or Fisher exact test were
performed to compare the differences in IIEF-5 scores
according to the MetS. Second, all subjects were analyzed the
simple relationships between IIEF-5 and age, phosphorus,
BMI, testosterone, PSA, and P V by the Spearman correlation
test. Third, we tested the relationship between IIEF and
phosphorus, PV after adjusting f or age, testosterone,
and MetS using multiple linear regression. Finally,
univariate and multivariate logistic regression analyses
were underwent to confirm the significance of age, PSA,
testosterone, phosphorus, BMI, P V, and MetS as predictors of
signif icant ED (IIEF-5 score ≤11).
The variables were considered statistically signif icant
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Min et al
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when p<0.05. We used the SPSS v er. 12.0 (SPSS I nc., Chicago,
IL, USA) for statistical analyses.
RESULTS
1. Patient characteristics according to IIEF-5 degree
The clinical characteristics of the 1,899 men are summa-
rized in Table 1. The median value of age, testosterone, and
phosphorus were 53.0 years, 4.58 ng/mL, and 3.50 mg /dL,
respectively. The median BMI was 24.8 kg/m2
, and 33.5% of
all patients had MetS. The median IIEF-5 score was 18. To
analyze dif f erences in erectile f unction according to many
clinical factors, we divided questionnaire groups into 3
subgroups by the degree of severity (Table 1). In the results,
patients with moderate to severe ED had relatively older
age, higher phosphorus level, and larger PVs than other
two groups (p<0.001, p=0.004, p=0.002, respectively ). Other
continuous variables were insignificantly diff erent between
the three groups. And, moderate to severe ED patients had a
higher prevalence of MetS (p=0.021) than other groups.
2. Correlations between IIEF-5 and clinical factors
This findings of the statistical analyses are shown in
Table 2. Significant correlation was not f ound between
IIEF-5 and BMI (r=–0.031, p=0.189), testosterone (r=0.033,
p=0.148), o r PS A ( r=– 0.007, p=0.769). IIEF-5 was re vealed
to have a positive correlation with PV (r=–0.065, p=0.004).
In addition, age (r= –0.238, p<0.001) and phosphorus level
(r=–0.108, p<0.001) were significantly related to IIEF. Serum
phosphorus level had the highest correlation with IIEF-5
except age, f ollowed by PV.
However, as shown in Table 3, phosphorus and PV were
not signif icantly correlated with IIEF af ter ad justing f or
age. The relationship of IIEF-5 with phosphorus and PV
remained insignif icant after adjusting for other confounding
factors (testosterone and MetS).
3. Predictive variables for moderate to severe ED
(logistic regression analysis)
Phosphorus, age, and MetS were f ound to be predictors
for moderate to severe ED in the univariate analysis (p=0.007;
OR , 1.108; 95% CI, 1.180 –1.137; p <0.001; OR, 1.125; 95% CI , 1.093 –
1.159; and p =0.010; O R, 1.372; 95% C I, 1.078–1.745, resp e c t i v e l y ).
And, testosterone, PSA, BMI, and P V were not predictive
factors for ED. Phosphorus, age, and MetS were independent
predictive factors for moderate to severe ED (p=0.048; OR,
1.101; 95% CI , 1.076 –1.131; p<0.0 01; OR , 1.119; 95% CI , 1.08 6– 1.153;
and p=0.048; OR, 1.283; 95% CI, 1.0 03 1.641, re s pec t i v e l y ) i n
the multivariate analysis (Table 4).
Table 1. Patients’ characteristics according to IIEF-5 degree (n=1,899)
Variable No or mild (17–25) Mild to moderate (12–16) Moderate to severe (≤11) p-value
Age (y) 51.4±4.8 52.8±4.3 54.0±4.0 <0.001
Body mass index (kg/m2) 24.8±2.4 25.1±2.4 25.0±2.6 0.151
Testosterone (ng/mL) 4.8±1.4 4.6±1.3 4.7±1.4 0.088
PSA (ng/mL) 0.96±0.95 0.96±0.76 1.00±1.28 0.726
Phosphorus (mg/dL) 3.40±0.46 3.50±0.44 3.71±0.50 0.004
PV (cm3) 23.9±6.8 25.2±7.0 24.4±7.1 0.002
MetS 341 (31.4) 159 (34.0) 136 (39.4) 0.021
Values are presented as mean±standard deviation or number (%).
IIEF-5, International Index of Erectile Function-5; PSA, prostate-specific antigen; PV, prostate volume; MetS, metabolic syndrome.
Table 2. Spearman correlations of IIEF-5 score with age, phosphorus, testosterone, PSA, and PV
Variable Phosphorus BMI IIEF-5 Testosterone PSA PV
Age 0.155 (<0.001) –0.026 (0.260) –0.238 (<0.001) 0.065* (0.004) 0.100 (<0.001) 0.215 (<0.001)
Phosphorus –0.010 (0.673) –0.108 (<0.001) –0.061 (0.008) 0.010 (0.673) –0.016 (0.008)
Body mass index –0.031 (0.189) –0.158 (<0.001) –0.044 (0.062) 0.210 (<0.001)
IIEF-5 0.033 (0.148) –0.007 (0.769) –0.065* (0.004)
Testosterone 0.077* (0.001) 0.006 (0.800)
PSA 0.335 (<0.001)
Values are presented as correlations coefficient (p-value).
IIEF-5, International Index of Erectile Function-5; PSA, prostate-specific antigen; PV, prostate volume.
*p<0.005. p<0.001.
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Phosphorus and erectile dysfunction
DISCUSSION
In this study, we demonstrated that phosphorus is
significantly related to IIEF. Serum phosphorus level had the
highest correlation coef f icient with IIEF-5, and the severity
of ED was greater in patients with elevated phosphorus
levels. In the multivariate analysis, we also found that age,
MetS, and phosphorus are independent predictive factors of
moderate to severe ED.
The IIEF is, today, one of the most commonly used f orms
for men presenting with sexual complaints. On the IIEF,
ED is classified from mild to severe [17]. To date, this is the
first research to study the association between phosphorus
and ED. It is also the first study to evaluate that association
using IIEF score and a detailed prostate work-up. Even af ter
multivariate logistic regression analysis including traditional
ED conf ounding factors, we revealed that phosphorus is a
meaningful predictive factor of severe ED.
In previous
in vitro
studies, hyperphosphatemia leads
a phenotypic converting vascular smooth muscle cells to
osteoblast-like cells that generate biochemical markers of
bone lineage, for example, Runx2, creating calcification
[18]. Furthermore, excessive phosphorus diet has been
appeared to induce endothelial dysfunction in young age,
and a phosphorus-enr iched medium induces bov ine aortic
endothelial cells to generate greater amounts of reactive
oxygen species [19]. One nephrology study group [5] revealed
that higher serum phosphorus level, even in the normal
range, had independent association with the occurrence of
coronary vessel calcif ication fifteen years later in young
adults with normal renal function. Recently, in Korea,
one study group demonstrated that a higher phosphorus
concentration, even within a normal value, may be related
with higher coronary vessel calcification in healthy adults,
and the effects did not change given racial or regional
dif f erence [20]. Except in cases with CAD, Yao et al. [21]
said that high phosphorus level causes calcif ication in
great vessel through the inf luence of β-catenin in subjects
with chronic kidney disease. Recent evidence has proposed
that the serum phosphorus is associated with clinical and
subclinical CVD in the normal population and it may differ
by gender [22,23]. In addition, high serum phosphorus levels
had an association between carotid intima-media thickness
and CVD risks in males, but not in females [22,23]. This
relationship may be related to declines in endogenous
estradiol that occur during the menopausal transition in
Table 3. Multiple linear regression test of IIEF-5 score with phosphorus level and prostate volume
Variable IIEF-5
Beta Standard error p-value
Phosphorus
Model 1 0.035 0.303 0.115
Model 2 0.039 0.304 0.087
Model 3 0.041 0.304 0.071
Prostate volume
Model 1 0.006 0.021 0.778
Model 2 0.007 0.021 0.761
Model 3 0.012 0.021 0.607
IIEF-5, International Index of Erectile Function-5; MetS, metabolic syndrome; model 1, adjusting for age; model 2, adjusting for age and testoster-
one; model 3, adjusting for age, testosterone, and MetS.
Table 4. Logistic regression analysis predicting the moderate to severe erectile dysfunction (IIEF-5≤11)
Variable Univariate Multivariate
p-value OR 95% CI p-value OR 95% CI
Age <0.001 1.125 1.093–1.159 <0.001 1.119 1.086–1.153
PSA 0.430 1.045 0.936–1.167 - - -
Testosterone 0.642 0.980 0.902–1.066 - - -
Phosphorus 0.007 1.108 1.080–1.137 0.048 1.101 1.076–1.131
Body mass index 0.506 1.017 0.968–1.067 - - -
Prostate volume 0.789 1.002 0.986–1.019 - - -
MetS (non-MetSa vs. MetS) 0.010 1.372 1.078–1.745 0.048 1.283 1.003–1.641
IIEF-5, International Index of Erectile Function-5; OR, odds ratio; CI, confidence interval; PSA, prostate-specific antigen; MetS, metabolic syndrome.
a:Reference value.
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women. In a large cohort of community-living Italians,
Cirillo et al. [24] demonstrated that at the age 45–50 years,
there was a signif icant increase in serum phosphorus and
a comparable decrease in urinary phosphorus excretion
in females, but not males. And, in a large population of
older men, serum estradiol levels and phosphorus levels
were inversely correlated, independent of kidney f unction,
vitamin D levels, parathyroid hormone concentration, and
bone density [25].
Vascular calcification and endothelial dysfunction are
both related to the atherosclerotic process, and obstruction of
atherosclerotic sites are closely associated with calcifications
of vascular endothelium [26]. There are several hypotheses
on the pathophysiology of ED as a sentinel marker of
vascular dysfunction. The artery size hypothesis stipulates
that ED is an early symptom of systemic atherosclerosis
[27]. Assuming that atherosclerosis progresses in all major
vascular beds at a relatively similar pace, those authors
argued that symptoms will manifest earlier in the smaller
arterial branches such as the penile artery rather than in
the larger vessels of the heart and limbs, which are able
to better tolerate the same degree of atherosclerosis or
obstruction [27]. In accordance with this hypothesis, Rogers
et al. [28] found that the degree of stenosis in the internal
pudendal arteries was similar to that found in the coronary
artery (52% to 65%) and that the average diameter of the
internal pudendal artery was just slightly smaller than
the average diameter of the coronary artery. Hamur et al.
[29] reported that CAD may increase as the severity of ED
increases. This also implies that the increased atherosclerotic
plaque burden in patients with stable CAD is systemic and
may be associated with endothelial dysfunction, especially
when the fact that patients with severe ED and stable
CAD may have high Syntax scores is taken into account. In
clinical practice, phosphorus levels in men are not routinely
measured prior to a health work-up and treatment. In view
of this point, our study underlines the usefulness of serum
phosphorus measurement in the health screening process as
a pre dict or of ED.
This study has some limitations. First, it has the disad-
vantages inherent in a retrospective design. Therefore, this
study was not including the various factors af f ecting erectile
function in men such as insulin-like growth f actor-1, several
cytokines, and C-reactive protein. Second, the cross-sectional
design rules out the evaluation of causality and may have
temporality among the variables. Third, our study cannot
rule out the possibility that outcomes were affected by
phosphorus intake and, consequently, that personal dietary
habits might disrupt the relation between phosphorus
levels and morbidity rates. Finally, in this study, we did not
observe the vitamin D and parathyroid related parameters.
However, our sample size was relatively large and
mostly homogeneous. And it did not include subjects with
chronic kidney disease. We also excluded subjects who
were taking drugs affecting prostate physiology, who used
phosphodiesterase-5 inhibitors daily or nutrients that
might adjust mineral or bone metabolism. There have been
no reported cross-sectional studies evaluating the role of
phosphorus as a predictive factor of ED. We suggest that
serum phosphorus level is a nontraditional potential risk
factor of ED in the healthy men. In modern society, we
tend to intake less of natural meal and more of processed
it. Processed foods usually have high-phosphate additives
and may af f ect phosphate intake more than recommended
amounts [30]. Known harmful effects of a high-phosphate
diet on the body is not enough to be well understood. Given
the increasing evidence of relationship between phosphorus
and several metabolic diseases, prospective well-designed
studies are required. In that study, interventions reducing
phosphate intake, such as restriction of dietary phosphorus
and adjustment of f ood additives, have to be included. They
can reduce the rates of metabolic diseases including ED in
high-risk patients or in the healthy population in the f uture.
Nowadays, there are no established guidelines f or serum
phosphorus intake in the general population. Managing
the causes of increased serum phosphorus and thereby
correcting elevated serum phosphorus levels in individuals
may be a relevant therapeutic target in preventing the
excess risk of ED. Future studies, however, should confirm
the causality of the relationship between the simultaneous
existence of serum phosphorus and the risk of ED. In
addition, basic research into all types of minerals and ED
merits further investigation.
CONCLUSIONS
Age, MetS, and phosphorus levels are significantly
associated with ED. We found that, in clinically stable
middle-aged men, serum phosphorus was strongly associated
with ED. And, recommended serum phosphorus levels could
be different for males than for females. Given this finding,
handling of phosphorus in men may have a particular
meaning of reducing the risk of ED.
CONFLICTS OF INTEREST
The authors have nothing to disclose.
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Phosphorus and erectile dysfunction
ACKNOWLEDGMENTS
This study was supported by a Korean National Police
Hospital Grant.
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... Vascular calcification described as abnormal calcium salts deposition in valvular and vascular tissue and is one of the most common effects of macrovascular complications in patients in aging, with chronic kidney disease and diabetes [1][2][3][4][5]. It leads to high mortality and morbidity worldwide [1][2][3]. ...
... Vascular calcification described as abnormal calcium salts deposition in valvular and vascular tissue and is one of the most common effects of macrovascular complications in patients in aging, with chronic kidney disease and diabetes [1][2][3][4][5]. It leads to high mortality and morbidity worldwide [1][2][3]. Uncovering the pathogenesis associated with cardiovascular calcification will be helpful to the design of new target molecules or a new therapeutic strategy for the treatment of vascular calcification. ...
... Vascular calcification development is a complex and active process associated with many signaling pathways [21]. Wnt/β-catenin signaling pathway has been implicated in aortic valve calcification and other calcification processes [2,4,21]. Activation of the Wnt/β-catenin signaling pathway leads to vascular cell calcification [2,4,21]. ...
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Vascular calcification is one of the most common effects of macrovascular complications in patients in aging with chronic kidney disease and diabetes. Previous studies showed that HOTAIR attenuated vascular calcification via the Wnt/β-catenin-signaling pathway, yet the molecular mechanism has not been fully elucidated. This study aimed to identify the explicit molecular mechanism underlying HOTAIR regulated vascular calcification. In the phosphate (Pi)-induced calcification model of human aortic smooth muscle cells (HASMCs), we investigated whether HOTAIR was involved in the regulation of miR-126. The luciferase reporter was used to examine the effect of HOTAIR on miR-126 and miR-126 on Klotho 3ʹ-UTR. Furthermore, we overexpressed Klotho to verify the regulation of Klotho on SIRT1, as well as their roles in mediating Pi-induced calcification in HASMCs via the Wnt/β-catenin signaling pathway. Finally, the results were verified in an in vivo mice calcification model. Overexpression of HOTAIR reduced the expression of miR-126 in Pi-induced HASMCs. Additionally, knockdown of miR-126 increased SIRT1 expression by regulating Klotho expression. An increased level of Klotho inhibited Wnt/β-catenin signaling pathway, which eventually attenuated Pi-induced HASMCs calcification. Luciferase reporter assay revealed that HOTAIR targeted miR-126 and miR-126 could directly target Klotho. Eventually, HOTAIR overexpression reversed Pi-induced calcium calcification in vivo mouse models. This study demonstrated that HOTAIR overexpression attenuated Pi-induced calcification by regulating the miR-126/Klotho/SIRT1 axis, thereby inhibiting the Wnt/β-catenin signaling pathway. It provides new potential target genes for the clinical treatment of vascular calcification.
... found to be positively correlated with the severity of erectile dysfunction, the inability to get or maintain an erection [12]. Low testosterone production and abnormal sperm function in CKD [13,14] or excess phosphorus [15,16] have also been observed. ...
... A high serum phosphate concentration is a common complication in the progress of CKD. Both CKD and hyperphosphatemia have adverse effects on fertility [12,13]. Therefore, this study hypothesized that phosphate would aggregate CKD-induced negative reproductive outcomes, in turn confirming the importance of phosphate restriction in CKD to achieve a better male fertility and life quality. ...
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Hyperphosphatemia is a serious complication in chronic kidney disease (CKD) that occurs due to insufficient excretion of phosphorus during failure of renal function. Both CKD and an excessive phosphorus intake have been reported to increase oxidative stress and result in poor male fertility, but little is known about the reproductive function of the CKD under a poorly controlled phosphate intake. Eight-week-old C57BL/6 mice (n = 66) were randomly divided into four groups: a sham operation group received a chow diet as control (SC group, n = 14), CKD-induced mice received a chow diet (CKDC group, n = 16), control mice received a high phosphorus (HP) diet (SP group, n = 16), and CKD-induced mice received a HP diet (CKDP group, n = 20). CKD was induced by performing a 5/6 nephrectomy. The chow diet contained 0.6% phosphorus, while the HP diet contained 2% phosphorus. Impaired testicular function and semen quality found in the CKD model may result from increased oxidative stress, causing apoptosis and inflammation. The HP diet aggravated the negative effects of testicular damage in the CKD-induced mice.
... [32]. However, a recent cross-sectional study from Korea did not nd a signi cant correlation between serum phosphorus and T in middle-aged men with erectile dysfunction [33]. These differences in results might be accounted for by different ages, races, genders, or diseases. ...
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Purpose: Serum phosphorus is reported to be associated with insulin resistance (IR) and testosterone in many populations. However, studies exploring the role of serum phosphorus in polycystic ovary syndrome (PCOS) patients are rare. Thus, we aimed to investigate the associations of serum phosphorus concentrations with IR and hyperandrogenemia (HA) in women with PCOS. Methods: This was a secondary analysis of a multicenter and large-sample clinical trial including 1000 PCOS subjects diagnosed by the modified Rotterdam criteria. A total of 508 normal-weight PCOS patients with available serum phosphorus data were enrolled in the present study. Serum phosphorus, metabolic indices, and total testosterone (TT) concentration were measured. IR status was defined by a homeostasis model assessment of insulin resistance (HOMA‐IR) ≥ 2.69, and HA status was defined as a TT level ≥ 1.67 nmol/L. Multivariable linear regression and logistic regression models were used to evaluate the associations of serum phosphorus with IR and HA. Results: Multiple linear regression analysis showed that the serum phosphorus concentration was inversely correlated with fasting plasma glucose (FPG), fasting insulin (FIN), HOMA‐IR, and TT (P trend < 0.05 for all) after adjusting for confounding factors. Logistic regression showed that the serum phosphorus concentration was negatively correlated with IR and HA status. The multivariable-adjusted odds ratios with 95% confidence intervals for IR and HA status for the lowest vs. the highest quartiles of serum phosphorus were 2.26 (1.17-4.35, P trend = 0.009) and 2.58 (1.48–4.51, P trend = 0.002), respectively. Conclusion: Our results demonstrated that lower serum phosphorus concentrations were associated with higher risk of IR and worsened HA in normal-weight women with PCOS.
... Several reports have demonstrated high serum phosphate levels in cardiac calcification and bone diseases, as previously described in this work. In addition, the level of phosphorus has been found to be positively correlated with a predictive factor for erectile dysfunction and the inability to obtain or maintain an erection [64]. ...
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Inorganic phosphate (Pi) is an essential nutrient for living organisms and is maintained in equilibrium in the range of 0.8-1.4 mM Pi. Pi is a source of organic constituents for DNA, RNA, and phospholipids and is essential for ATP formation mainly through energy metabolism or cellular signalling modulators. In mitochondria isolated from the brain, liver, and heart, Pi has been shown to induce mitochondrial reactive oxygen species (ROS) release. Therefore, the purpose of this review article was to gather relevant experimental records of the production of Pi-induced reactive species, mainly ROS, to examine their essential roles in physiological processes, such as the development of bone and cartilage and the development of diseases, such as cardiovascular disease, diabetes, muscle atrophy, and male reproductive system impairment. Interestingly, in the presence of different antioxidants or inhibitors of cytoplasmic and mitochondrial Pi transporters, Pi-induced ROS production can be reversed and may be a possible pharmacological target.
... In other aspects, for example, men who work nonstandard shifts and have poor sleep quality are at increased risk for hypogonadal symptoms and sexual dysfunction [31]. Serum inorganic phosphorus had the highest correlation coefficient with IIEF-5 score in the middle-age [32]. ...
Article
Objective: To analyze the impact of age, BMI and sex hormone on aging males’ symptoms (AMS) and the 5-item version of the international index of erectile function (IIEF-5) scores in middle-aged and elderly Chinese men. Methods: A population-based cross-sectional study was conducted in Jiashan County. A total of 969 men, aged between 40 and 80 years old, were admitted. Physical examination and the sex hormones were measured, and AMS and IIEF-5 scores were assessed. Results: The oneway ANOVA analysis indicated older age groups had higher AMS total-scores, somatic and sexual sub-scores, and lower IIEF5 scores (all p < .01). Pairwise correlation (rpairwise) analyses showed the significant associations between AMS and age or sex hormone (cFT, Bio-T, SHBG, and LH) levels, and similar for IIEF5. However, when age was adjusted, the correlation coefficients (rpartial) weakened, and correlation significance disappeared, except LH (for AMS: rpartial = 0.096, p = .009; for IIEF-5: rpartial = −0.140, p = .001). Multiple linear regressions confirmed the influence of increased age and LH on the AMS and IIEF5 scores. Conclusion: CFT, Bio-T and SHBG failed to yield any additional predicting information when age was adjusted. To improve the male reproductive health, future research should pay more attention on aging-related comorbidities and how to improve general wellness.
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Background Whether there is a connection between sexual dysfunction (SD) and prostate cancer (PCa) is controversial. Aim We sought to review the interrelationship between SD and PCa and to determine whether there is a definitive risk of men developing PCa after suffering from SD. Methods A complete search of the PubMed, Web of Science, Ovid MEDLINE, Embase, and Cochrane Library databases was performed to search for eligible studies published up to October 2022. The protocol for this meta-analysis is available from PROSPERO (ID: CRD42022342381). Outcomes The associations between SD and the risk of PCa were assessed by calculating pooled ORs with 95% CIs, and the standard mean difference (SMD) and its 95% CI were used to assess the relationship between SD and prostate-specific antigen (PSA) levels or prostate volume (PV). Random-effects models were used to account for potential heterogeneity, and the Newcastle–Ottawa Scale (NOS) was used to evaluate the quality of the included studies. Results Twenty studies involving 215,626 individuals were included in our meta-analysis. Compared with controls, subjects with SD had a 1.62-fold increased risk of PCa (OR = 1.62, 95% CI, 1.77-2.23, P = .003; heterogeneity: I2 = 97.8%, P < .001). Patients with SD had higher PSA levels than controls (SMD =0.07, 95% CI, 0.00 to 0.13, P = .041; heterogeneity: I2 = 55.6%, P = .027). However, there was no association between SD and PV (SMD = 0.03, 95% CI, −0.05 to 0.11, P = .122; heterogeneity: I2 = 48.5%, P = .100). Clinical Implications Current evidence confirms a potential link between SD and the risk of PCa and that SD in PCa patients should be of concern to clinicians. Strengths and Limitations The strength of this study is that it is to our knowledge the first meta-analysis of studies on the risk of PCa in men with SD. A limitation is that most of the studies included in this meta-analysis focused on ED. Conclusion Our systematic review and meta-analysis results suggest that men with SD have a higher risk of PCa and higher PSA levels than men without SD. However, this is merely inferential, and causality cannot be determined based on the current data. Further longitudinal studies should be performed to validate our preliminary findings.
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This chapter will focus on the diagnostic work around sexual dysfunction in Parkinson's disease, especially laboratory tests and biomarkers. A number of methods to analyze if sexual dysfunction is caused by neural pathology, vascular dysfunction or other mechanisms are now available. Other methods can be used to differentiate between psychogenic/functional reasons behind sexual dysfunction and organic ones. The role of biomarkers for diagnosis, but also for understanding the reason behind and for counteracting sexual dysfunction is becoming more evident. There is also a rich and increasing number of scales and other instruments available for detecting and quantifying sexual hypo- and hyperactivity. When investigating the reason behind sexual dysfunction in patients with Parkinson's disease comorbidities should also be considered. Finally, early and pronounced sexual dysfunction might in some cases be an indication that differential diagnosis, like Multisystem Atrophy, should be thought about. All these aspects of the diagnostic procedures around sexual dysfunction in Parkinson's disease will be covered in this chapter.
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PurposeTestosterone (T) plays an important role in men’s health and its deficiency is linked with poorer health. However, the role of nutritional and lifestyle factors in T regulation and production remains unclear. The objectives are to comprehensively test the cross-sectional associations of nutritional and lifestyle factors with T deficiency and to validate the associations in the NHANES survey.Methods We performed weighted multivariable logistic regression analysis to examine the association of 173 nutritional and lifestyle factors with T deficiency (total testosterone ≤ 3.5 ng/mL) in NHANES III as the discovery set (mean age 41). We controlled for multiple comparisons with a false discovery rate (FDR) < 5% and replicated in NHANES 1999–2004 (mean age 44).ResultsWe identified seven nutritional factors as being inversely associated with T deficiency in NHANES 1999–2004, namely dietary intake of vitamin A, protein, saturated fatty acids, monounsaturated fatty acids, total fats, saturated fatty acid 16:0, and phosphorus. In a multivariable model, only vitamin A intake remained significantly associated with T deficiency (OR 0.97, 95% CI 0.94–0.99). Principal component analysis suggested that the two principal components, (1) dietary fats, protein, and phosphorous and (2) total vitamin A, may be associated with T deficiency.Conclusion Our systematic evaluation provided new insight into the modifiable factors that could play a role in the regulation of T production. This study has the potential to contribute to the current body of literature which seeks to formulate a clinical definition of T deficiency after taking into account nutritional and lifestyle factors.
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Growing evidence reports that obesity might play a role in erectile dysfunction (ED), but limited knowledge is available. We conducted a meta-analysis to estimate the prevalence of ED in overweight men and men with obesity. We performed a systematic review up to 01/04/2019 to investigate the associations between obesity and ED. Applying a random-effect model, we calculated the prevalence of ED, the odds ratio (OR) for the presence of ED by Body Mass Index (BMI) categories and the mean differences between ED and controls in BMI and Waist Circumference (WC). Among 3409 studies, we included 45 articles with 42,489 men (mean age = 55 years). Taking normal weight men as reference, the prevalence of ED was significantly higher in overweight (OR = 1.31; 95%CI: 1.13–1.51; I2 = 72%) and in men with obesity (OR = 1.60; 95%CI: 1.29–1.98; I2 = 79%). Adjusting our analyses for potential confounders, the results were confirmed in men with obesity (OR = 1.46; 95%CI: 1.24–1.72; I2 = 72%). ED was associated with significant higher values of BMI (MD = 0.769; 95%CI: 0.565–0.973 Kg/m2; I2 = 78%) and WC (MD = 5.251 cm; 95%CI: 1.295–9.208; I2 = 96%). Considering the high prevalence of ED among men with obesity, clinicians should screen for this clinical condition in this population. Findings from the present study suggest that reducing adiposity is a crucial approach in patients with ED who are affected by obesity.
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Serum phosphorus (P) concentration is associated with coronary artery calcification (CAC) as well as cardiovascular events in patients with chronic kidney disease. It has been suggested that this relationship is extended to subjects without renal dysfunction, but further explorations in diverse races and regions are still needed. We performed a cross-sectional study of 2,509 Korean subjects (Far Eastern Asian) with an estimated glomerular filtration rate of ≥60 ml/min/1.73m2 and who underwent coronary computerized tomography. Serum P concentration was divided into pre-determined 4 categories: ≤3.2, 3.2< to ≤3.6, 3.6< to ≤4.0 and >4.0 mg/dL. Agatston score (AS), an index of CAC, was divided into 3 categories: 0, 0< to ≤100, and >100. A multinomial logit model (baseline outcome: AS = 0) was applied to estimate the odds ratio (OR) for each serum P category (reference: ≤3.2mg/dL). Mean age of subjects was 53.5±9.1 years and 36.9% were female. In the adjusted model, serum P concentration of 3.6< to ≤4.0 mg/dL and >4.0 mg/dL showed high ORs for AS of >100 [OR: 1.58, 95% confidence interval (CI): 1.04-2.40 and OR: 2.11, 95% CI: 1.34-3.32, respectively]. A unit (mg/dL) increase in serum P concentration was associated with 50% increase in risk of AS >100 (OR: 1.50, 95% CI: 1.16-1.94). A higher serum P concentration, even within a normal range, may be associated with a higher CAC in subjects with normal renal function.
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Insulin resistance (IR) triggers endothelial dysfunction, which contributes to erectile dysfunction (ED) and cardiovascular disease. To evaluate whether IR was related to ED in young adult patients. A total of 283 consecutive men complaining of ED at least six months were enrolled, with a full medical history, physical examination, and laboratory tests collected. Quantitative Insulin Sensitivity Check Index (QUICKI) was used to determine IR. The severity of ED was assessed by IIEF-5 questionnaire. Endothelial function was assessed by ultrasonographic examination of brachial artery flow mediated dilation (FMD). IR was detected in 52% patients. Subjects with IR had significant higher total cholesterol, triglycerides, low density lipoprotein-cholesterol (LDL-c), glycated haemoglobin (HBA1c), high sensitivity C-reactive protein (hs-CRP) and body mass index (BMI), but showed significant lower IIEF-5 score, FMD%, high density lipoprotein -cholesterol (HDL-c), testosterone, sex hormone binding globulin (SHBG) levels than patients without IR. Multiple regression analysis showed QUICKI and testosterone were independent predictors of IIEF-5 score. Furthermore, the incidence of IR was correlated with the severity of ED. Compared with other CVFs, IR was found as the most prevalent in our subjects. Besides, IR was independently associated with ED and its severity, suggesting an adverse effect of insulin resistance on erectile function.
Article
Introduction: Erectile dysfunction (ED) and coronary artery disease (CAD) are closely related as a result of endothelial dysfunction leading to the restriction of blood flow. ED is a potential independent risk factor of CAD. We investigated the prevalence and severity of ED, the extent of CAD and the time interval between the symptoms of ED and CAD in the stable coronary artery patients. Materials and methods: 161 patients applied coronary angiography were divided into two groups according to SYNTAX score as group 1 (n=81) SYNTAX score ≤22, and group 2 (n=80) SYNTAX score >22. The prevalence and severity of ED was determined by using The International Index of Erectile Function (IIEF). Results: The prevalence of ED was 43.2% in group 1 and 61.3% in group 2 (P=0.022). The score of IIEF was 23.1 (15-29) in group 1, 19.3 (6-29) in group 2; there was a significant difference (P=0.000). In the multivariate logistic regression analysis carried out in order to determine the independent predictors on Syntax score, it was found that LDL (odds ratio: 1.032, 95% confidence interval: 1.009-1.055, P=0.007) and IIEF score (odds ratio: 0.825, 95% confidence interval: 0.733-0.928, P=0.001) were the independent predictors. The time between the symptoms of ED and CAD 30.1 ± 4.8 months in group 1, and 40.5 ± 4.3 months in group 2 (P=0.000). Conclusion: The severity of ED is an independent factor predicting the extent of CAD. The early detection of ED enables to make a cardiovascular evaluation. Therefore, taking the cardiovascular risk factors under an aggressive treatment may contribute to prevent the cardiovascular cases which may develop in the future.
Article
Vascular calcification is a risk factor for causing cardiovascular events and has a high prevalence among chronic kidney disease (CKD) patients. However, the molecular mechanism underlying this pathogenic process is still obscure. Vascular smooth muscle cells (VSMCs) were induced by a concentration of phosphorus (Pi) of 2.5 mM, and were subjected to cell calcification analyses. The effect of high Pi on the Wnt/β-catenin pathway was measured using a TOP/FOP-Flash reporter assay. The transcriptional regulation of β-catenin on PIT1 (a type III sodium-dependent phosphate cotransporter) was confirmed by promoter reporter and chromatin immunoprecipitation assays. The 5/6 nephrectomized rat was used as an in vivo model and was fed a high Pi diet to induce aortic calcification. Serum levels of phosphate, calcium, creatine, and blood urea nitrogen were measured, and abdominal aortic calcification was examined. High Pi induced VSMC calcification, downregulated expression levels of VSMC markers, and upregulated levels of osteogenic markers. High Pi activated the Wnt/β-catenin pathway and β-catenin activity. β-Catenin was involved in the process of high Pi-induced VSMC calcification. Further investigation revealed that β-catenin transcriptionally regulated Pit1, a necessary player in VSMC osteogenic phenotype change and calcification. The in vivo study showed that β-catenin was involved in rat abdominal aortic calcification induced by high Pi. When knockdown expression of β-catenin in the rat model was investigated, we found that aortic calcification was reduced. These results suggest that β-catenin is an important player in high phosphorus level-induced aortic calcification in CKD. © 2015 S. Karger AG, Basel.
Article
The regulation of serum phosphate, an acknowledged risk factor for chronic kidney disease and cardiovascular mortality, is poorly understood. The discovery of fibroblast growth factor 23 (FGF23) as a key regulator of renal phosphate handling and activation of vitamin D has revolutionized our comprehension of phosphate homeostasis. Through as yet undetermined mechanisms, circulating and dietary phosphate appear to have a direct effect on FGF23 release by bone cells that, in turn, causes renal phosphate excretion and decreases intestinal phosphate absorption through a decrease in vitamin D production. Thus, the two major phosphaturic hormones, PTH and FGF23, have opposing effects on vitamin D production, placing vitamin D at the nexus of phosphate homeostasis. While our understanding of phosphate homeostasis has advanced, the factors determining regulation of serum phosphate level remain enigmatic. Diet, time of day, season, gender, age, and genetics have all been identified as significant contributors to serum phosphate level. The effects of these factors on serum phosphate has major implications for what is understood as “normal” and for studies of phosphate homeostasis and metabolism. Moreover, other hormonal mediators such as dopamine, insulin-like growth factor, and angiotensin II also affect renal handling of phosphate. How the major hormone effects on phosphate handling are regulated and how the effect of these other factors are integrated to yield the measurable serum phosphate are only now beginning to be studied.This article is protected by copyright. All rights reserved
Article
Introduction: Various studies report increased risk of erectile dysfunction (ED) in men with cardiovascular (CV) disease and postulate an intimate nexus between the two conditions. Aim: To examine the association of ED with CV risk factors and disease in a population-based cross-sectional observational study conducted in Western Australia (WA). Method. Postal questionnaires were sent to randomly selected age-stratified male population samples obtained from the WA Electoral Roll. Main outcome measures: In addition to items covering sociodemographic and self-reported clinical information, the 5-item International Index of Erectile Function (IIEF-5) was used. Results: Of the 1,580 participants, the ages of 1,514 were known and ranged from 20 to 99 years (mean 57.9, median 59.1, standard deviation 18.5). CV risk factors and disease were more prevalent with increasing age and among participants with ED and severe ED. The age-adjusted odds of ED were significantly higher among participants with hypertension (odds ratio [OR] 1.47; 95% confidence intervals [CI] 1.05, 2.07), ischemic heart disease (OR 1.80; 95% CI 1.10, 2.94), and stroke (OR 3.30; 95% CI 1.22, 8.88), and with these conditions and peripheral arterial disease grouped together as CV disease (OR 1.85; 95% CI 1.34, 2.56). Many participants with hyperlipidemia were receiving treatment, and the age-adjusted odds for ED were not significantly higher. The age-adjusted odds of ED among participants with diabetes mellitus were 2.76 (95% CI 1.52, 5.00), and were 3.21 (95% CI 1.03, 10.05) when hypertension and hyperlipidemia were also present. Conclusions: The findings support the postulated intimate nexus between ED and CV disease. The adverse effects of age and CV risk factors and disease on erectile function compound each other. The socioeconomic, epidemiologic, and clinical implications are immense.
Article
To describe the angiographic characteristics of pelvic arterial disease in patients with erectile dysfunction (ED) nonresponsive to phosphodiesterase-5 inhibitors (PDE5i) and suspected coronary artery disease (CAD). ED and CAD share common risk factors which can result in endothelial dysfunction, atherosclerosis and flow-limiting stenoses in the coronary and internal pudendal arteries. Ten patients undergoing cardiac catheterization with ED and a history of unsatisfactory response to a PDE5i were studied. ED severity was quantified using the International Index of ED scoring system. We performed angiography and quantitative vessel analysis of the coronary arteries, bilateral common and internal iliac arteries, and internal pudendal arteries (IPAs). In this pilot observational study, we found a high correlation between the presence of angiographic CAD and IPA disease. The reference IPA diameters at the point of maximal stenosis were 2.7 ± 0.4 mm (right IPA) and 2.7 ± 0.5 mm (left IPA). In the nine patients with IPA disease, the average stenosis severity was 55 ± 31% (right) and 66% ± 25% (left), and average lesion length was 12.4 ± 5.2 mm (right) and 10.0 ± 3.5 mm (left). Four patients had unilateral IPA total occlusions, three of whom had moderate contralateral disease. The majority of IPA stenoses occurred in the mid to distal IPA and appears amenable to percutaneous revascularization. This represents the first angiographic report of CAD correlated with IPA disease in patients with ED. Further investigation is required to determine whether the development of macrovascular disease in the IPA causes ED and whether endovascular treatment is safe and effective in this population.
Article
Postmenopausal women consistently have higher phosphorus levels than similarly aged men. As it is known that estradiol induces phosphaturia in rodents, we evaluated the cross-sectional association of sex hormones with serum phosphorus in 1346 community-living older men (mean age 76) of which 18% had moderate (stage 3) kidney disease. Using linear regression with serum phosphorus levels as the dependent variable, we found that for each 10 pg/ml higher total estradiol level there was a statistically significant 0.05 mg/dl lower serum phosphorus when adjusted for age, ethnicity, testosterone, sex hormone-binding globulin, calcium, estimated glomerular filtration rate, intact parathyroid hormone, 25(OH) vitamin D, bone mineral density, and alkaline phosphatase. These results were similar in individuals with or without chronic kidney disease. Serum testosterone concentrations were also statistically significantly associated with lower serum phosphorus levels. We confirmed these results in an independent sample of 2555 older men, wherein these associations were not attenuated when adjusted for fibroblast growth factor-23 levels. Hence, our study of community-living older men suggests that estradiol may directly or indirectly induce phosphaturia in humans. The mechanism responsible for the association of testosterone with serum phosphorus remains to be determined.