JOURNAL OF ENDOUROLOGY

Volume 24, Number 7, July 2010

ª Mary Ann Liebert, Inc.
Pp. 1183–1187
DOI: 10.1089=end.2010.0113

Serum Testosterone May Be Associated

with Calcium Oxalate Urolithogenesis

Justin M. Watson, M.D.,1 Adam B. Shrewsberry, M.D.,1 Shaya Taghechian, M.D.,1 Michael Goodman, M.S. M.P.H.,2
John G. Pattaras, M.D.,1 Chad W.M. Ritenour, M.D.,1 and Kenneth Ogan, M.D.1

Abstract
Background: The incidence of urolithiasis is twofold to threefold higher in men than in women. Several animal
studies have suggested an association between testosterone levels and the formation of kidney stones. Specifi-
cally, castration has been shown to decrease stone formation in rat models. The association between testosterone
and stone formation in humans, however, has not been well investigated.
Patients and Methods: Early morning total and free testosterone levels were recorded for 55 male patients.
Participants completed a demographics questionnaire, and clinical records of enrolled subjects were reviewed.
When available, stone composition was determined in the stone formers. Mann-Whitney tests and logistic
regression models were used to examine the data.
Results: Of the 55 patients, 25 had no history of urolithiasis and 30 had a history of urolithiasis. Although the
differences between the two groups were not statistically significant, the stone formers compared with stone-free
controls tended to be older (median age 48.4 vs 36.5 years, P ¼ 0.072) and have higher serum levels of testos-
terone (median serum concentration 384 vs 346 ng=dL, P ¼ 0.112). In the multivariate analyses, after adjusting for
age and body mass index, the testosterone-related odds ratio was 1.004 with a corresponding P value 0.051.
Conclusions: Male stone formers were found to have higher serum total testosterone levels compared with a
similar cohort without stones. This result is consistent with several animal models that have demonstrated that
testosterone is a risk factor for stone formation. Our findings warrant confirmation in a larger, prospective study.
There are potential therapeutic implications if testosterone is found to be a risk factor in urolithogenesis.

Introduction men.13–15 Each of these observations supports a role for sex

hormones in lithogenesis. In addition, experimental studies in

U rinary calculi are a common occurrence worldwide,

with a lifetime risk of 10% to 15%.1 Moreover, the inci-
dence of urinary tract stones has increased in the United States
between 1976 and 1994.2,3 After initial stone presentation, 50%
of patients will form more stones within 5 to 10 years, and 75%
of these patients will have recurrences within 20 years.4,5
It is well established that urolithiasis occurs with greater
frequency in males. The relative frequency has been noted to
be three times that of women in multiple studies, and the rate
of formation of idiopathic calcium stones has been reported to
be four to five times higher in men than in women.6–10 This
sexual disparity seems to be influenced by age. Interestingly,
stone formation in the prepubescent population is similar
between males and females.11 The greatest difference in idio-
pathic calcium oxalate stone formation is seen in the third and
fourth decade of life.12 In the sixth decade of life, stone inci-
dence, as well as testosterone levels, begin to decline in
rats have demonstrated both that testosterone promotes
stone formation and that estrogen inhibits stone formation,
although the mechanisms remain unclear.16,17
Our hypothesis is that higher serum testosterone levels are
a risk factor for the development of urolithiasis. As such, we
sought to prospectively test whether total and free serum
testosterone levels were higher in male stone formers com-
pared with a similar control cohort of nonstone-formers.
Patients and Methods
Enrollment of study subjects
Fifty-five men older than 18 years were enrolled in this
study that was approved by the Emory University Institu-
tional Review Board. All subjects were prospectively enrolled
at the department of urology in the Emory Clinic from April
2006 to January 2010. Thirty of the subjects had a history of

1
Department of Urology, Emory University School of Medicine, Atlanta, Georgia.
2
Department of Epidemiology, Emory University School of Public Health, Atlanta, Georgia.

1183
1184
calcium-oxalate stones (stone formers) and 25 had no history
of stones (controls). Patients were excluded from the study if
they had primary hyperparathyroidism, chronic diarrheal
syndromes, intestinal malabsorption, complete distal renal
tubular acidosis, primary hyperoxaluria, recurrent or active
urinary tract infection, history of kidney transplantation, on-
going 5-a reductase inhibitor therapy, liver disease, primary
gout, any debilitating chronic illness, or a calculated creati-
nine clearance of
50 mL=minute.
Study protocol
One serum sample was drawn from each subject in the
morning between 8AM and 11 AM. All patients underwent
anthropometric measurements that allowed calculation
of their body mass index (BMI). Patients were asked to
self-identify their race=ethnicity and to complete a health
questionnaire, which inquired about the family history of
urolithiasis.
Assays
Blood samples were centrifuged immediately and stored at
28C to 38C until assayed. Serum total testosterone was ana-
lyzed by Quest laboratory (San Juan Capistrano, CA) by using
turbulent flow liquid chromatography tandem mass spec-
trometry18 and percent free was assessed by tracer equilib-
rium dialysis.19 From these data, the free testosterone level
was calculated.
Statistical analysis
The distributions of variables under study were compared
in the two groups (urolithiasis patients and controls) using the
Mann-Whitney rank sum test for continuous variables and the
chi-square test for categorical variables. Logistic regression
analyses were performed to examine the association between
testosterone and kidney stones while controlling for possible
confounding because of differences in age and BMI between
the groups. The results of the logistic regression analyses were
expressed as odds ratios (OR) accompanied by 95% confi-
dence intervals (CI) and P values. All statistical analysis was
performed using SPSS (version 17.0) software (SPSS, Inc,
Chicago, IL).
Results
As shown in Table 1, stone-forming patients were not sta-
tistically different from the stone-free controls with respect to
Table 1. Univariate Comparison of Patients With and Without Urolithiasis
All patients
Variable N ¼ 55
Non-Hispanic Caucasians, N (%) 42 (76.4)
Family history of urolithiasis, N (%) 27 (49.1)
Age (years), median (range) 40.4 (19.7–72.7)
BMI (kg=m2), median (range) 26.7 (19.4–37.0)
Total testosterone (ng=dL), median (range) 353 (190–865)
Free testosterone (pg=mL), median (range) 58.2 (27.9–123.3)
a
Based on Mann-Whitney test for continuous variables and chi-square test for dichotomous variables.
BMI ¼ body mass index.
WATSON ET AL.
ethnicity (76.7 vs 76.0% of non-Hispanic whites, P ¼ 0.954) and
family history of kidney stones (53.3% vs 44.0%, P ¼ 0.491).
The median BMI was 26.8 kg=m2 among patients with a his-
tory of stones and 26.6 kg=m2 among controls (P ¼ 0.389).
Although none of the differences between the two groups
were statistically significant, the stone-forming patients
compared with stone-free controls were older (median age
48.4 vs 36.5 years, P ¼ 0.072) and had higher serum levels of
testosterone (median serum concentration 384 vs 346 ng=dL,
P ¼ 0.112). In contrast to the total testosterone results, there
was no difference with respect to free serum testosterone
(P ¼ 0.919).
In the multivariate analyses, after adjusting for age and
BMI, the testosterone-related OR was 1.004 (95% CI: 1.000–
1.009) with a corresponding P value of 0.051 (Table 2). This
reflects an increase in the likelihood of being a stone former for
each increase of one unit of ng=dL of serum total testosterone.
The OR shown for age and BMI are not statistically significant.
Discussion
Early investigations into the differences in stone formation
between sexes noted that men had a higher rate of urinary
excretion of oxalate,2,20 an important promoter of lithogen-
esis, and women had a higher rate of urinary excretion of
citrate,21–23 an important inhibitor of lithogenesis. Recent
work has begun to elucidate possible mechanisms by which
testosterone may affect these and other pathways leading to
urolithogenesis.
Sex hormones are thought to alter oxalate metabolism,
leading to increased lithogenesis in men (Fig. 1). Glycolic acid
oxidase (GAO) is an oxalate-producing enzyme that is part
of the pathway in converting ethylene glycol to oxalate.
Richardson and associates24 showed that testosterone in-
creases the activity of GAO by an unclear mechanism. Con-
versely, estrodiol has been shown to decrease GAO activity.25
Lee and colleagues16,17 compared the rate of calcium oxalate
stone formation of normal male rats, castrated male rates,
normal female rats, and castrated female rats fed a lithogenic
ethylene glycol diet. They found that uncastrated male rats
excreted the highest levels of oxalate and the uncastrated fe-
male rats excreted the lowest levels. Not surprisingly, cases of
urolithiasis occurred in the ethylene glycol fed intact male rats
but not female rats. In addition, castration of male rats dra-
matically decreased the incidence of renal stones. Further-
more, subcutaneous implantation of exogenous testosterone
restored calcium oxalate stone formation in postorchiectomy
male rats and enhanced stone formation in intact female rats.
Stone formers Normal volunteers
N ¼ 30 N ¼ 25 P-valuea
23 (76.7) 19 (76.0) 0.954
16 (53.3) 11 (44.0) 0.491
48.4 (20.7–72.7) 36.5 (19.68–67.72) 0.072
26.8 (19.7–36.4) 26.6 (19.4–37.0) 0.389
384 (214–865) 346 (190–659) 0.116
58.0 (27.9–123.3) 62.8 (31.5–104.7) 0.919
TESTOSTERONE MAY BE ASSOCIATED WITH UROLITHOGENESIS 1185

Table 2. Logistic Regression Analysis of the Association Between Urolithiasis

and Patients’ Age, Total Testosterone, and Body Mass Index

Variable Unadjusted ORa (95% CI), P-value Adjusted ORa (95% CI), P-value

Age, years 1.034 (0.995–1.074), 0.084 1.032 (0.991–1.074), 0.127

BMI, kg=m2 1.082 (0.936–1.251), 0.286 1.128 (0.959–1.328), 0.147
Total testosterone, ng=dL 1.003 (0.999–1.008), 0.102 1.004 (1.000–1.009), 0.051

Logistic regression model includes all variables in the table.

a
odds ratio reflects increase in the likelihood of kidney stone per unit of each variable.
OR ¼ odds ratio; CI ¼ confidence interval; BMI ¼ body mass index.

The authors state that these findings support the hypothesis
that testosterone plays a determinant role in the pathogenesis
of calcium oxalate stone formation.
Another mechanism by which sex hormones affect the
rate of stone formation is via their effects on expression of
osteopontin (OPN). OPN, a 44 kD renally secreted acidic
phosphorylated glycoprotein,26,27 has been shown to be a
macromolecular in vivo inhibitor of calcium oxalate crystalli-
zation.28 OPN synthesis has also been shown to be upregu-
lated in experimental urolithiasis models induced by ethylene
glycol supplemented diets in rats.29 More evidence that
OPN is involved in urolithogenesis is the link between an
OPN genetic polymorphism and formation of urinary cal-
cium stones reported by Gao and coworkers.30 Importantly,
Yagisawa and associates31 used a rat model to demonstrate
that OPN expression in the kidney is suppressed in the
presence of testosterone and promoted by the presence of
estrogen. This contributes further to the evidence that hor-
mones are involved in urolithogenesis.
There is a paucity of research into the relationship between
sex hormones and urolithogenesis in humans, with only two
publications noted on review of the literature. In the first
study, Van Aswegen and colleagues32 examined human tes-
tosterone levels and their relationship to stone formation by
investigating total urinary testosterone and renal calculi in
16 healthy participants. The authors demonstrated that uri-
nary testosterone levels were lower in patients who had a
history of kidney stones. Because of the proposed endocrine

FIG. 1. Proposed influence of sex hormones on urolithogenesis. DHT ¼ dihydrotestosterone; GAO ¼ glycolic acid oxidase;
OPN ¼ osteopontin.
1186
(eg, via GAO) mechanism of sex hormone influence on
lithogenesis, however, examination of urine testoster-
one levels is less than ideal to investigate the role that se-
rum testosterone levels play in the physiology of stone
formation.
In the second of these studies, Tiselius and colleagues33
demonstrated, in a series of castrated men with prostate
cancer, that there was no significant change in urinary oxalate
excretion despite a decrease in plasma testosterone. However,
the mean age was 71 years, thus introducing grounds for
questioning the magnitude of the effect, given our lack of
knowledge of the in vivo enzyme kinetics of GAO. There was
also little attention paid to standardizing or quantifying ox-
alate intake. Our study seeks to answer the question of whe-
ther stone-forming men have higher testosterone levels than
nonstone-forming controls.
Currently, interventions for stone prevention consist pri-
marily of increased water intake, diet alterations, urine alka-
linizing agents, thiazides, and allopurinol.34,35 If testosterone
contributes to stone formation, however, perhaps testosterone
may also be targeted to enhance stone prevention. In partic-
ular, 5-a reductase inhibitors may provide a way to effectively
target dihydrotestosterone (DHT) levels to provide stone
prophylaxis. In fact, the use of finasteride to decrease urinary
oxalate excretion has already been described in male rats.36
This implies that DHT and testosterone may both play a role
in the pathway of stone formation.
Our analyses showed that after controlling for age and
BMI, total serum testosterone levels were higher in the group
with a history of urolithiasis. This is consistent with our
hypothesis that testosterone may play a pivotal role in
urolithogenesis in men. Free testosterone levels, however, did
not statistically differ between the two groups. The free tes-
tosterone level was directly measured, but there is debate over
the most reliable method of assay. Furthermore, there is no
experimental evidence to suggest that free testosterone con-
centration is specifically relevant to urolithogenesis. There-
fore, it is difficult to draw conclusions regarding the lack of
difference in free testosterone concentrations between our
patient populations.
Several limitations of this study should be noted. The small
sample size and lack of age-matched populations of cases and
controls has not prevented us from drawing statistically valid
conclusions but may limit the ability to detect other differ-
ences, such as differences in free testosterone or impact of
family history of urolithiasis. Also, the use of single sample-
based serum assays prevented us from taking into consider-
ation diurnal as well as day-to-day variation in testosterone
levels. In addition, there is a lack of consensus on what
magnitude of difference in testosterone levels is sufficient to
imply clinical significance.
Previous animal research has reported a direct correlation
between serum testosterone concentrations and urinary oxa-
late excretion.32,36 Therefore, another limitation of this study is
the absence of 24-hour urine studies. Finally, our participants
were predominantly non-Hispanic Caucasian (42=55, 76.4%),
and thus our results cannot be extrapolated to other ethnic
groups. This is important because of known ethnic variation in
the rate of stone formation, such as described lower rates of
stone formation in the African American population.37
We believe that our findings indicate a need for further
study, possibly prospectively following a large cohort of
WATSON ET AL.
patients on whom testosterone levels are recorded and re-
porting the incidence of stone formation.
Conclusions
In this small pilot study, a higher total serum testosterone
level was found in stone-forming men than in nonstone-
forming controls. This finding is consistent with several ani-
mal models that have demonstrated that testosterone is a risk
factor for stone formation. This should be studied in a pro-
spective fashion on a larger scale to further elucidate the as-
sociation between serum testosterone levels and urolithiasis
in humans. A significant association may have relevant ther-
apeutic implications.
Acknowledgment
The work on this publication was supported in part by
the funds from the Atlanta Clinical & Translational Science
Institute.
Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Kenneth Ogan, M.D.
Department of Urology
Emory University School of Medicine
1365 Clifton Rd, Suite B
Atlanta, GA 30322
E-mail: kenneth_ogan@emoryhealthcare.org
Abbreviations Used
BMI ¼ body mass index
CI ¼ confidence interval
DHT ¼ dihydrotestosterone
GAO ¼ glycolic acid oxidase
OPN ¼ osteopontin
OR ¼ odds ratio