Research Manuscript
Is Polycystic Ovarian Syndrome a Risk Factor for Urinary Stone Disease?
Xinguo Zhu*, Ikbal Kaygusuz, Ayla Eser, Mehmet Erol Yildirim, Ersin Çimentepe, Ebru Yüce and Kadir Çetinkaya
Department of Obstetrics and Gynecology, Etlik Lokman Hekim Hospital, China
*Corresponding author: Xinguo Zhu, Department of Obstetrics and Gynecology, Etlik Lokman Hekim Hospital, China
Published: 11 May, 2018
Cite this article as: Zhu X, Kaygusuz I, Eser A, Yildirim
ME, Çimentepe E, Yüce E, et al. Is
Polycystic Ovarian Syndrome a Risk
Factor for Urinary Stone Disease?. Clin
Oncol. 2018; 3: 1443.
Abstract
Urinary stone disease is a multi factorial disorder and a complex process influenced by both intrinsic
and environmental factors with an approximate prevalence of 1% to 15% worldwide that varies
depending on elements such as age, sex, race, and genetic factors. In animal and human studies,
testosterone has been shown to increase the formation of urinary stones. This suggests that sex
hormones are involved in the pathogenesis of stone disease. Hyperandrogenism, the main feature
of Poly Cystic Ovary Syndrome (PCOS), may trigger the urinary stone formation besides hirsutism,
alopecia and acne. The present study was performed to investigate whether patients with PCOS
were at risk in terms of urinary system stone disease. Forty patients with PCOS and 40 healthy
controls were included in the study, after exclusions the study ended up with 38 patients (PCOS
group n=23, control group n=15). 24-hr urinary composition, biochemical and hormonal levels
were analyzed. 24-hr excretion of oxalate was statistically significantly higher in the PCOS subjects
than control group. Patients with PCOS had higher urinary uric acid and lower citrate levels than
control subjects. There was no difference for urinary calcium levels between the PCOS and control
groups. PCOS may trigger the urinary stone disease.
Keywords: Urinary stone disease; Polycystic ovary syndrome; Urinary oxalate; Urinary uric acid; Urinary citrate; Urinary calcium
Introduction
Urinary stone disease is a multi factorial disorder and a complex process influenced by both
intrinsic and environmental factors with an approximate prevalence of 1% to 15% worldwide that
varies depending on elements such as age, sex, race, and genetic factors. Males have a three times
higher incidence compared to females in the reproductive stage, but there is no gender difference in
childhood or climacterium. In males it occurs in the third and fourth decades of life when the level
of serum testosterone is also the highest [5]. In women during the sixth decade of life a time that
corresponds to the onset of menopause with a fall of estrogen levels, the incidence of urinary stone
disease increases [6].
Furthermore, men have higher urinary calcium, oxalate and uric acid excretions than women
which promote lithogenesis and lower urinary citrate excretion which inhibits crystal growth and
aggregation [15,20]. Compared with men, urinary calcium is lower in women until age 50 years,
when it equals that of men. Citrate is equal in the genders until the age 60 years, when it tends to
decrease in women [20]. Estrogen replacement increases urinary citrate excretion in postmenopausal
women [4].
These all support the role of sex hormones in urinary stone formation. In animal and human
studies, it has been shown that androgens appear to have a boosting effect and estrogens appear to
have a inhibitory effect on urinary stone formation [7-10,12-14,16-19].
Polycystic ovarian syndrome (PCOS) is one of the most common endocrine disorders
encountered in 5%-10% of reproductive- age women [11]. It is a heterogeneous condition,
characterized by hyperandrogenism and ovulatory dysfunction that consists of anovulation or
polycystic ovarian morphology. The principle features of PCOS are hyperandrogenism and insulin
resistance which can augment hyperandrogenism [1]. It is a major cause of menstrual disturbances,
female anovulatory infertility and clinical signs of androgen excess including hirsutism and acne
[2]. Moreover, PCOS is associated with long-term health risks, including cardiovascular disease,
diabetes mellitus, hypertension, endometrial carcinoma [2,3].
It’s a known fact for many years that urinary stone disease is
more frequently seen in men depending on the hyperandrogen
levels. However it’s not studied in patients with PCOS which is
associated with high serum androgen levels. It is hypothesized that
PCOS accompanied by hyperandogenism may be a risk factor in the
formation of urinary stone disease.
Table 1
Table 2
Materials and Methods
This cross sectional study was performed at the Medical School
of Turgut Özal University, Ankara, Turkey between 2013 and 2016
years. A total of 23 newly diagnosed patients were identified as PCOS
cases according to the Androgen Excess Society (AES) criteria [1],
while 15 healthy volunteer women (regularly menstruating, nonhirsute,
normo-ovulatory, without any infertility) were recruited in
the study as the control group.
AES criteria are based on two abnormalities: hyperandrogenism
and ovarian dysfunction after the exclusion of other pathologies with
a similar clinical presentation such as congenital adrenal hyperplasia,
Cushing’s syndrome, androgen-secreting tumours, hypothyroidism
and hyperprolactinemia. Hyperandrogenism was defined either
clinical (hirsutism with a modified Ferriman-Gallwey score of >6,
acne, alopecia) and/or biochemical (free serum testosterone level
of >2.7 pg/mL and/or total testosterone level of >80 ng/dL) signs of
hyperandrogenism. Oligo and/or anovulation (cycle length irregular,
>35 days or <8 periods per year), or polycystic ovary morphology
(presence of at least one ovary of more than 10 ml size and/or with
at least 12 follicles of 2 mm to 9 mm diameter) is accepted the two
manifestations of ovarian dysfunction.
Exclusion criteria were as follows: pregnancy, hypothyroidism,
hyperprolactinemia, congenital adrenal hyperplasia, cushing
syndrome, androgen-secreting tumors, hypertension, diabetes,
hyper¬parathyroidism, adrenal, hypophyseal or any systemic diseases
such as sarcoidosis that alter calcium homeostasis, hypercalcemia,
current or previous (within the last 6 months) use of calcium, vitamin
D supplementation, hormonal medications, diuretics, antiacids, H2
blockers, antihypertensive drug, obesity (body mass index [BMI]
>30), smokers. Positive history or positive family history of urinary
stone disease, so no graphically proven urinary stones, positive
urine culture, incomplete 24 hr urine collection, impaired renal
function (serum creatinine >1.5 mg/dL) and patients with anatomical
anomalies of the urinary tract were also other exclusion cirteria.
This study was approved by the Turgut Ozal University Ethical
Committee and complied with the Helsinki Declaration. All women
signed written informed consent before the start of the study. This
work is supported by the Scientific Research Fund of Turgut Ozal
University under project number 2013_04_006.
A complete physical examination was performed on all subjects.
BMI was calculated as weight in kilograms divided by the square of
the height in meters (kg/m2) for all subjects.
Hormonal assays and transvaginal ultrasonography were
performed during the early follicular phase, between the 3rd and
the 5th days of the patients’ spontaneous or progestin-induced
menstrual cycle. The sonographic evaluations of the kidneys and
urinary tract systems and the diagnosis and detection of urinary
stone were performed by the same radiologist. Venous blood samples
of the participants were collected in the morning subsequent to an
overnight fast from the antecubital vein, and 24-hr urine was collected
(after 3 days of diet restricting strawberry, chocolate, ice cream,
meat, fish, spinach, asparagus, tomato, cucumber) and calcium,
sodium, potassium, chloride, oxalate, urea, citrate, cysteine, uric acid,
magnesium, creatinine, and phosphorus levels were measured. 24-hr
urine analysis and fasting serum biochemistry (creatinine, uric acid,
urea, calcium, magnesium) as well as intact PTH and 1,25(OH)2D3
was performed at the same time.
Complete Blood Count (CBC), fasting blood glucose, fasting
insulin, hormone profile, lipid profile, were measured. IR was
determined from fasting glucose and insulin as homeostasis model
assessment–insulin resistance (HOMA-IR) index: HOMA-IR =
[glucose (mmol/l) × insulin (mIU/l)]/22.5. Oral glucose tolerance test
(OGTT) with 75 gr glucose was applied to all patients.
CBC analysis was performed in a Beckmann-Coulter analyzer
model LH -780 with optical scattering method. Blood glucose, total
cholesterol, High-Density Lipoprotein (HDL) and Triglyceride (TG),
serum creatinine, uric acid, urea, calcium and magnesium were
measured by spectrophotometric method on a Roche Cobas 6000
series-c501 device (Roche Diagnostics, Tokyo, Japan). Low-Density
Lipoprotein (LDL) was calculated with use of the Friedewald formula.
Insulin, Follicle Stimulant Hormone (FSH), Luteinizing Hormone
(LH), Estradiol (E2), Dehydroepiandrosterone Sulphate (DHEAS),
Total Testosterone (TT), Thyroid Stimulating Hormone (TSH),
and prolactin (PRL) were determined by Electrochemiluminesans
(ECLIA) method using a Roche Cobas 6000 series-e601 device (Roche
Diagnostics, Tokyo, Japan). 17-OH Progesterone was measured by
a radioimmunoassay (RIA) method with DiaSource (Catalog No.
KIP1409) kit in Ankalab Laboratory. 25OH cholecalciferol was
measured by HPLC method using a UV detector on Zivak ONH-
100A device (Istanbul, Turkey).
Urine calcium, sodium, potassium, chloride, urea, uric acid,
magnesium, creatinine, and phosphorus were measured by
spectrophotometric method on a Roche Cobas 6000 series-c501
device (Roche Diagnostics, Tokyo, Japan). Urine oxalate, citrate,
cysteine were measured by spectrophotometric method on a Roche
MIRA Plus analyzer (Roche Diagnostic Systems Welwyn Garden
City, Herts) using a commercial kit in Ankalab Laboratory.
Statistical analysis was performed using Statistical Package for
the Social Sciences (SPSS) version 16.0 for Windows XP. Continuous
variables were first inspected for normality of statistical distribution
graphically and by Shapiro-Wilk test. The data are presented as
mean ± Standard Deviation or median with inter quartile ranges, as
appropriate. Clinical characteristics, serum laboratory parameters
and urinary biochemical parameters were compared in each group.
The data were analyzed using the Student’s t-test or Mann-Whitney
test to determine whether differences were significant. The correlation
between variables was investigated using Pearson correlation test
(Spearman test). P<0.05 was considered statistically significant.
Table 3
Results
A total of 80 cases including 40 PCOS and 40 control patients
were taken into the study. Seventeen cases were lost to follow-up
(n=5, PCOS group, n=12 control group). Two cases had hemolysis
in the blood (n=1, PCOS group, n=1 control group). Two cases had
abnormal biochemical levels (n=2 control group). Twelve cases had
abnormal hormonal levels (n=5, PCOS group, n=7 control group).
Nine cases had inadequate or incorrect urine collection (n=6, PCOS
group, n=3 control group). As a result, the study ended up with 38
subjects (PCOS group n=23, control group n=15).
There were no differences in age and BMI between the analyzed
groups. Biochemical and endocrine features of PCOS and control
groups are summarized in Table 1. As expected, serum LH, TT,17-
OH Progesterone, DHEAS, fasting insulin HOMA-IR, total
cholesterol and LDL cholesterol levels were significantly higher in
the PCOS group (p = 0.001, 0.02, 0.04, 0.001, 0.01, <0.01, 0.02, 0.02;
respectively) (Table 2).
The urinary comparison of the subjects in both groups is shown
in Table 3. When we compare the urinary composition of the groups,
24-hr excretion of oxalate levels were significantly higher in the PCOS
subjects than control group (p=0.04). While urinary oxalate levels
were found above the normal reference range in 3 PCOS patients,
only 1 woman in control group had higher levels. Patients with PCOS
had a higher urinary uric acid and lower citrate levels than control
subjects, but there was no statistical significance (p>0,05). While
urinary citrate levels were found above the normal reference range
in 1 PCOS patients, 6 woman in control group had higher levels.
No difference was determined between the groups for 24-hr urinary
excretion of calcium, sodium, potassium, chloride, urea, magnesium,
creatinine, phosphorus, and cysteine levels (p>0,05).
Discussion
In the present study, we found that 24-hr urinary excretion of
oxalate levels were higher in PCOS group than healthy controls.
Oxalate is a metabolic end product excreted in urine with no known
useful biological function in human. Glycolate is metabolized to
glyoxylate in liver peroxisomes, then metabolized to oxalate by
glycolate oxidase, the most important enzyme in the pathway. Sex
hormones have long been suspected of being etiologically important
in the formation of calcium oxalate stones.
Several previous experimental studies have disclosed that
androgens play a role in the etiopathology of urinary stone disease,
for reason stone disease is more common in men than in women.
Yoshihara et al. reported a gender-related difference in the metabolic
conversion of glycolate to oxalate in rats, a process dose-dependently
promoted by testosterone [17]. Their results also showed that
estrogen decreases glycolate oxidase activity in male rats. Lee et al.
Have shown that castrated male rats have a remarkable reduction in
stone formation after drinking an ethylene-water solution and have
indicated that testosterone promotes renal crystal deposition because
glycolic acid oxidase is involved in the metabolism of ethylene glycol
to oxalate which may be enhanced by testosterone [10], resulting in
hyperoxaluria, which in turn may be responsible for the increased
predisposition to calcium oxalate urolithiasis [7]. In the rat ethylene
glycol model of urolithiasis Dihydrotestosterone (DHT) is believed to
be partially responsible for exaggerated hyperoxaluria [8]. Yagisawa
et al. investigated the effect of castration on urinary lithogenic factors
and renal osteopontin expression in rats treated with ethylene glycol
and reported that while testosterone increased oxalate excretion
in urine by suppressing osteopontin expression in the kidneys and
promote stone formation, estrogen decreased oxalate excretion in
urine by increasing osteopontin expression [16]. In another rat study
Yoshioka et al. showed that sex hormones increased endogenous
oxalate synthesis by affecting hepatic peroxisomal enzymes and renal
tubular epithelial cells exposed to excessive oxalate causes oxidative
stress injury that results in DNA damage to cells and initiates crystal
formation [18].
In clinical studies Watson et al. reported that male stone formers
(n=30) have higher serum total testosterone levels than stone-free
controls (n=25) [19], Nath et al. Reported a positive correlation
between serum testosterone with urinary oxalate in male stone
formers [14]. Naghii et al. Analyzed the effect of steroid sex hormones
in the plasma samples including testosterone, free testosterone,
dihydrotestosterone, estradiol, and sex hormone binding globülin in
renal stone patients and found higher androgen levels that indicate
a possibility of a substantial pathogenic role of testosterone, free
testosterone, and dihydrotestosterone in the pathogenesis of renal
stones formation [13].
Androgenic hormone can modulate their effect through changes
in their serum levels, or in the sensitivity or activity of their receptors.
Defined an up-regulation in androgen receptors in the kidneys of
patients with urolithiasis and linked the intergender difference of
incidence to this condition [12].
Increased urinary excretion of uric acid is another risk factor
for calcium stone disease that can form the nidus for calcium stone
configuration. Heller et al. found lower daily excretion of urinary uric
acid in women than men [9]. Unlike in another study, Shakhssalim
et al. found no significant difference for testosterone and estradiol
between the male active renal calcium stone formers and control
groups serum testosterone was related to higher urinary excretion
of uric acid in patients so postulated the possibility of testosterone
involvement in the pathogenesis of renal stones through higher
urinary uric acid and oxalate excretion [15]. In the present study 24-
hr urinary excretion of oxalate levels were higher in PCOS group than
healthy controls but we found no statistical significance (p=0.07).
Urinary citrates have a chelating activity against calcium ions
regarded as an inhibitor of calcium-containing stone formation.
Urinary citrate levels are clearly lower in stone formers than in
healthy adults and in women than men [15]. In our study we found
lower urinary citrate levels in PCOS group than healthy subjects.
As a result in our study we found statistically significantly higher
urinary oxalete levels, higher urinary uric acid levels and lower
urinary citrate levels which promote lithogenesis in PCOS patients
than healthy controls suggesting the effect of testosterone. Small
sample size of our study may have caused non-significant results in
urinary uric acid and citrate levels. Hyperandrogenism, the main
feature of PCOS, may trigger the urinary stone formation besides
hirsutism, alopecia and acne. Early identification of the situation will
help to take protective measures in the PCOS patients.
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