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SERUM SEX STEROIDS DEPICT A NONLINEAR U-SHAPED ASSOCIATION WITH
HIGH-RISK PROSTATE CANCER AT RADICAL PROSTATECTOMY
Andrea Salonia, Firas Abdollah, Umberto Capitanio, Nazareno Suardi, Alberto Briganti, Andrea
Gallina, Renzo Colombo, Matteo Ferrari, Giulia Castagna, Patrizio Rigatti, Francesco Montorsi
Department of Urology, University Vita–Salute San Raffaele, Milan, Italy
RUNNING TITLE: Sex steroids are nonlinearly associated with high-risk PCa
KEY WORDS: prostate cancer; radical prostatectomy; testosterone; 17 estradiol; sex hormonebinding globulin
SOURCE OF FUNDING: none
CONFLICTS OF INTEREST: none
TEXT WORD COUNT: 3386
NUMBER OF TABLES: 3
NUMBER OF FIGURES: 3
CORRESPONDING AUTHOR:
Andrea Salonia, M.D.
Department of Urology
University Vita-Salute San Raffaele
Via Olgettina 60
20132 Milan, Italy
Tel. +39 02 2643 7286
Fax +39 02 2643 7298
Email: [email protected]
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STATEMENT OF TRANSLATIONAL RELEVANCE
Although a comprehensive serum hormonal milieu has scarcely been investigated in terms of
prediction of pathologic outcomes in patients undergoing radical prostatectomy, virtually all
previous reports assumed a linear relationship between the circulating hormonal milieu and the
examined end points. Based on this concept of linearity, especially in the relationship between
testosterone and prostate cancer, androgen deprivation therapy has always been confirmed as a
standard treatment for metastatic prostate cancer, with the specific purpose of completely breaking
down circulating testosterone levels and preventing any interaction with the various androgen
receptors. The findings of this exploratory analysis demonstrate, for the first time, that preoperative
serum total testosterone and estradiol levels and the total testosterone–estradiol ratio are
independent predictors of high-risk prostate cancer, defined using the NCCN guidelines, but they
depict a nonlinear U-shaped correlation (ie, both the lowest and the highest circulating levels of sex
steroids are significantly associated with high-risk prostate cancer). This innovative finding could
support the concept that the use of androgen deprivation therapy, as either a standard treatment for
metastatic prostate cancer or as an adjuvant systemic therapy for high-risk men, could be even
differently tailored according to the endocrine network at the root of the prostate cancer behavior,
thus potentially supporting the newly-developed and evolving hormonal therapy which is aimed at
reducing androgen signaling and controlling prostate cancer growth even in the presence of very
low circulating androgen levels. Likewise, current findings may also contribute to support the use of
androgen replacement therapy, which is undertaken commonly but cautiously in aging men with
testosterone deficiency syndrome, since testosterone substitution might be titrated to a 'safe' level.
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ABSTRACT
PURPOSE. Assess the association between preoperative serum total testosterone (tT), 17β
estradiol (E2), sex hormone–binding globulin (SHBG), and tT–E2 ratio values with high-risk
prostate cancer (PCa; as defined by the National Comprehensive Cancer Network practice
guidelines) at radical prostatectomy (RP).
METHODS. Serum E2, tT, and SHBG were dosed the day before surgery (7–11 AM) in a cohort of
724 candidates to RP. Restricted cubic spline functions tested the association between predictors
(ie, model 1: age, body mass index [BMI], and serum tT, E2, and SHBG levels; Model 2: tT–E2
values instead of tT and E2 levels) and high-risk PCa.
RESULTS. Low-, intermediate-, or high-risk PCa was found in 251 (34.7%), 318 (43.9%), and 155
(21.4%) patients, respectively. Patients in the high-risk class showed the lowest tT, E2, and tT–E2
ratio values (all p 0.02). At univariate analysis, only age, tT, E2, and tT–E2 ratio values were
significantly associated with high-risk PCa (all p 0.006). At multivariate analyses considering
model 1 variables, age (p = 0.03), serum tT (all p < 0.001), and E2 (all p 0.01) were associated
with high-risk PCa; only tT–E2 ratios achieved independent predictor status for high-risk PCa (all p
< 0.001) when considering model 2. Both the lowest and the highest tT, E2, and tT–E2 values
depicted a nonlinear U-shaped significant association with high-risk PCa.
CONCLUSIONS. These data showed that preoperative serum sex steroids are independent
predictors of high-risk PCa, depicting a nonlinear U-shaped association.
ABSTRACT WORD COUNT: 252
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INTRODUCTION
Data from several population-based studies failed to show a significant association between
circulating levels of androgens (including total testosterone [tT]) and increased risk of prostate
cancer (PCa) (1). In this context, despite long-held axiomatic convictions about T-centric and Tdependent prostate carcinogenesis (ie, the higher the level of circulating T, the greater the risk of
developing PCa), low serum tT levels, rather than high levels, were associated with an increased
risk of PCa in both animal and human studies (2-4).
Similarly, data on radical prostatectomy (RP) populations have shown no unambiguous evidence
reporting that preoperative circulating tT levels were associated with poor prognosis, including
increased stage at presentation (5,6), advanced pathologic stages (5-9), higher rate of positive
surgical margins (5,6), increased risk of biochemical failure (9.12), and worse survival (9,13).
Likewise, controversies still exist regarding the relationship between serum tT levels and Gleason
score; indeed, numerous studies (2,3,14-17) (but not all) (18) have reported low serum tT levels,
rather than high levels, in association with advanced or high-grade PCa at surgery. A
comprehensive serum hormonal milieu has scarcely been investigated in terms of prediction of
pathologic outcomes in patients undergoing RP, with significant controversial findings (19-24).
Virtually all previous reports assumed a linear relationship between the hormonal milieu and the
examined end points (5-17). Based on this concept of linearity, especially in the relationship
between T and PCa, androgen deprivation therapy (ADT) has always been confirmed as a standard
treatment for metastatic PCa (25), with the specific purpose of completely breaking down
circulating T levels and preventing any interaction with the various androgen receptors. However,
previous reports suggested that high tT values, as well as low tT values, may be associated with
adverse outcomes. This suggestion indicates a rather nonlinear relationship, with both extremes
(high and low) predicting worse outcomes.
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To test this hypothesis, we (1) analyzed the association between preoperative serum tT and highrisk PCa, as defined according to the National Comprehensive Cancer Network (NCCN) practice
guidelines stratification (26), in a large cohort of nonscreened white European PCa patients
undergoing RP at a single institution and (2) evaluated the association of 17β estradiol (E2), sex
hormone–binding globulin (SHBG), and tT–E2 ratio values with high-risk PCa in the same cohort
of men.
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MATERIALS AND METHODS
Patient population
The analyses were based on a cohort of 838 nonscreened Caucasian-European PCa patients who
underwent RP at a single academic referral center between June 2007 and May 2011. For the
specific purpose of this analysis, none of the patients had uncontrolled diabetes, thyroid disease,
hyperprolactinemia, hypoalbuminemia, or liver disease. Moreover, none of the patients had taken
any hormonal neoadjuvant treatment or other hormonal preparations during the previous 12 mo.
Symptoms of late-onset hypogonadism were not specifically collected for this cohort of men.
All patients were comprehensively assessed with a detailed preoperative evaluation, including age;
measured body mass index (BMI), defined as weight in kilograms by height in square meters; total
serum prostate-specific antigen (PSA; Abbott Axym PSA assay; Abbott Laboratories, Abbott Park,
IL, USA); biopsy Gleason sum; and clinical stage determined by a senior attending urologist,
according to the 2002 American Joint Committee on Cancer staging system (27). Hypogonadsm
was defined as tT <3 ng/ml (28).
For the specific purpose of this analysis, candidates for RP were stratified for their risk of
biochemical recurrence after definitive therapy according to the NCCN guidelines v.4.2011 (26)
into low risk (tumors stage T1 or T2a, Gleason score 6, and serum PSA level <10 ng/ml),
intermediate risk (tumors stage T2b or T2c, or Gleason score 7, or serum PSA level of 10–20
ng/ml), and high or very high risk (tumors stage T3a, or Gleason score 8–10, or serum PSA level
>20 ng/ml) of recurrence.
A total of 114 men were excluded because they lacked one or more of the entry criteria:
preoperative PSA was missing (n = 12; 1.4%), clinical stage was missing or imprecise (n = 46;
5.5%), biopsy Gleason was imprecise (n = 22; 2.6%), or measured preoperative BMI was missing
(n = 34; 4.1%). A sample of 724 patients (86.4%) was included in the analysis.
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The study was approved by the local ethics committee; likewise, the assay of this protocol was
approved by the local institutional review board. Informed consent was obtained from each patient
before enrollment after full explanation of the purpose and nature of all procedures used.
Hormone measurements
To reflect the common practice of a clinical biochemistry laboratory, we elected to measure
circulating hormones using commercially available analytic methods. In this context, a single
preoperative venous blood sample was drawn from each participant at least 4 wk after transrectal
ultrasound–guided prostate needle biopsy. Samples were drawn between 7
AM
and 11
AM
on the
day before surgery (29) and were kept at 4°C until serum was separated by centrifugation at 4°C.
Serum aliquots were then stored at 80°C until assay. In all cases, tT levels were measured via a
direct chemiluminescence immunoassay (ADVIA Centaur; Siemens Medical Solutions Diagnostics,
Deerfield, IL, USA); E2 was measured by a heterogeneous competitive magnetic separation assay
(Bayer Immuno 1 System, Bayer Corp., Tarrytown, NY, USA); and SHBG levels were measured
via a solid-phase, chemiluminescent immunometric assay on Immulite 2000 (Medical Systems
SpA, Genoa, Italy). The same laboratory was used for all patients. The intra- and interassay
coefficients of variation (CVs) were <6% and <8%, respectively, for both tT and E2. The intra- and
interassay CVs for SHBG were <5% and <6%, respectively.
Main Outcome Measures
The primary end point of this analysis was to assess whether serum tT levels were differently
distributed across NCCN guidelines risk classes in a nonscreened homogeneous cohort of
Caucasian-European patients undergoing RP. The secondary end point was to assess the behavior of
both circulating E2 and SHBG and tT–E2 ratio values in the same cohort of men according to
NCCN guidelines stratification.
Statistical analyses
Data are presented as mean (median; range). The statistical significance of differences in means and
proportions was tested with the one-way analysis of variance and the 2 trend test, respectively.
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Exploratory analyses were initially applied to all variables in a preliminary analysis, and variables
were then kept where appropriate as significant to the results. Logistic regression models tested the
association between predictors (eg, age; BMI; continuously coded tT, E2, SHBG levels; and tT–E2
values) and NCCN guidelines risk classes. Two models were developed: Model 1 included age,
BMI, and continuously coded tT, E2, and SHBG levels; model 2 included age, BMI, and tT–E2 ratio
values. Restricted cubic spline functions with three knots tested the potential nonlinear association
between predictors and high-risk PCa and were used to display the data graphically (30,31).
All statistical analyses were performed using the R statistical package (R Foundation for Statistical
Computing, Vienna, Austria). All tests were two-sided, with a significance level set at 0.05.
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RESULTS
Table 1 lists the characteristics and descriptive statistics of the entire cohort of patients. Table 2
reports the characteristics and descriptive statistics examined according to NCCN guidelines riskclass segregation. Patients in the high-risk class showed the lowest serum tT and E2 levels as well as
the lowest mean tT–E2 ratio (all p 0.02). In contrast, patients did not differ in terms of age, BMI,
and serum SHBG values (all p 0.05) across the classes of risk. Hypogonadism was found in 177
(24.4%) of the whole cohort of patients. Hypogonadal patients were significantly more frequent
across classes of increased risk (p 0.001) (Table 2).
Figures 1a–1c depict the relationship between predictors (eg, serum tT, E2, and tT–E2 values) and
high-risk PCa. In this context, high-risk PCa was significantly more frequent both for the lowest
and the highest circulating levels of serum tT and E2, depicting a nonlinear U-shaped risk
relationship (Fig. 1a and 1b). A similar finding was observed for the relationship between tT–E2
values and high-risk PCa (Fig. 1c). In contrast, the relationship of serum SHBG, age, and BMI with
high-risk PCa did not demonstrate similar behavior (Fig. 1d, Fig. 2, and Fig. 3).
According to univariate analysis, age at surgery, serum tT, E2, and tT–E2 ratio were significantly
associated with high-risk PCa (all p 0.006), whereas BMI and circulating SHBG values were not
(Table 3). At multivariate analyses, considering model 1 variables, patient age and circulating levels
of both tT and E2 achieved independent predictor status for high-risk PCa (all p 0.03), whereas
BMI and SHBG levels did not. Conversely, considering multivariate analyses for model 2 variables,
only tT–E2 ratio values achieved independent predictor status for high-risk PCa (p < 0.001) (Table
3). Both univariate and multivariate analyses confirmed the nonlinear U-shaped relationship
between the examined hormones and high-risk PCa, where the lowest (10th percentile) and highest
(90th percentile) values predisposed to a higher risk of more aggressive PCa (Table 3).
According to univariate analysis, age at surgery, serum tT, E2, and tT–E2 ratio were significantly
associated with low-risk PCa (all p 0.02), whereas BMI and circulating SHBG values were not
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(Table 3). At multivariate analyses, considering model 1 variables, circulating levels of tT achieved
independent predictor status for low-risk PCa (all p 0.001), whereas all other variables did not.
Conversely, considering multivariate analyses for model 2 variables, only tT–E2 ratio values
achieved independent predictor status for low-risk PCa (all p 0.04) (Table 3). Both univariate and
multivariate analyses confirmed the nonlinear inverse U-shaped relationship between the examined
hormones and low-risk PCa, where the lowest (<10th percentile) and highest (>90th percentile)
values predisposed to a lower probability of a low-risk PCa (Table 3).
According to univariate analysis, serum E2, and tT–E2 ratio were significantly associated with
intermediate-risk PCa (all p 0.02), whereas all the other variables were not (Table 3). At
multivariate analyses, considering model 1 variables, only circulating levels of E2 showed a trend
towards significance for intermediate-risk PCa (all p = 0.05), whereas all other variables did not.
Conversely, considering multivariate analyses for model 2 variables, only tT–E2 ratio values
achieved independent predictor status for low-risk PCa (all p 0.04) (Table 3) Both univariate and
multivariate analyses confirmed the nonlinear inverse U-shaped relationship between the examined
hormones and intermediate-risk PCa, where the lowest (<10th percentile) and highest (>90th
percentile) values predisposed to a lower probability of intermediate-risk PCa (Table 3).
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DISCUSSION
We tested whether preoperative circulating tT, E2, and SHBG levels and tT–E2 ratio values were
associated with high-risk PCa, defined according to the NCCN practice guidelines stratification, in
a large, homogeneous cohort of nonscreened Caucasian-European men undergoing RP at a single
academic institute. Our interest was fueled by the existing controversies regarding the role of
circulating sex steroids as established predictors of pathologic outcomes at RP, usually stemming
from the T-centric and T-dependent premise that there is a sort of linear relationship between the
hormonal milieu and the specific PCa outcome.
To the best of our knowledge, the findings of this exploratory analysis demonstrate, for the first
time, that preoperative serum tT and E2 levels and the tT–E2 ratio are independent predictors of
high-risk PCa, defined using the NCCN guidelines, but they depict a nonlinear U-shaped correlation
(ie, both the lowest and the highest circulating levels of sex steroids are significantly associated
with high-risk PCa). Conversely, these data showed that both BMI and SHBG levels are not
multivariate predictors of high-risk PCa.
One strength is that the current study was a single-institute survey with a large cohort of
nonscreened, homogeneous, same-race patients for which all laboratory assessments, surgical
procedures, and specimen evaluations were performed using a consistent method. A second strength
is that the patients included in this study presented a wide variety of low- and high-risk tumors,
possibly allowing for adequate variability in the baseline serum sex steroids to provide robust
analysis. Third, all blood samples were correctly drawn after an overnight fast between 7 AM and 11
AM
[level 2a, grade A (29)], thus avoiding a potential methodological flaw due to different
collection times and diurnal variation of the steroid hormones. A further strength is that we
rigorously excluded men with uncontrolled diabetes, thyroid disease, hyperprolactinemia,
hypoalbuminemia, or liver diseases as well as those patients who had taken any form of hormonal
preparation during the previous 12 mo (32). Similarly, the prevalence of hypogonadism was 24.4%
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within our cohort of patients and is comparable with prevalence estimates from other studies (33).
The latter observation certainly corroborates the validity of our cohort of men as a representative
sample of PCa patients, although the results of our exploratory analysis may be optimal for this
cohort of nonscreened patients. These results should be validated externally with men from
different countries or ethnic backgrounds.
Although contradictory findings have been reported, androgens are still believed to be critical
determinants in normal and neoplastic growth and development of the prostate (16). Likewise,
many data on RP populations have made it clear that there is a close correlation between circulating
androgens—including the value of T as well as the condition of hypogonadism—and pathologic
outcomes, although a unique direction that supports incontrovertible biology has not yet been
identified (5-18). Moreover, although androgens and estrogens both play significant roles in the
prostate, their specific balance seems to be even more critical in maintaining prostate health and
tissue homeostasis in adulthood. Collectively, animal data have revealed that elevated T in the
absence of estrogens may lead to the development of hypertrophy and hyperplasia of the prostate
gland but not to malignancy (34). In contrast, high estrogen levels and low T have been shown to
lead to the development of inflammation with aging and in premalignant lesions (34). Interestingly,
T is the major precursor of E2 in men via a conversion mediated by the P450 aromatase enzyme
(34,35). Aromatase is active in adipose tissue, adrenal glands, the testicles, and the prostate (22),
meaning that it acts as a potential key regulator of the ratio of androgens to estrogens within the
prostate (22,35). The local intraprostatic conversion of androgens to both reduced androgens and
estrogens (35) is certainly of major importance according to the presence and function of local
steroid metabolizing enzymes. Combined evidence supports the concept that aromatase expression
and activity in the prostate may be upregulated at the tumor site, eventually resulting in an altered
T-to-estrogen ratio. The almost complete lack of any observation of the potential significance of the
T-to-estrogen ratio as a predictor of high-risk PCa could further stigmatize the value of our
findings.
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Patient age emerged as an independent predictor of high-risk PCa at both univariate and
multivariate analysis considering model 1 variables; restricted cubic spline functions depicted a
trend toward a linear increase throughout years of age (Fig. 2). This result is coupled with the
available controversial data regarding the impact of age on PCa; indeed, it is often suggested that
older men are more likely to be diagnosed with high-risk PCa and subsequently have lower overall
survival (36). Interestingly, Pierorazio et al (9) recently showed that higher levels of serum free T
are associated with an increased risk of aggressive PCa among older men. In contrast, some data
support even less aggressive PCa in older men (37).
Our analysis found that preoperative BMI did not achieve independent predictor status for high-risk
PCa, although restricted cubic spline functions depicted a sort of U-shaped correlation (Fig. 3). Our
findings contrast with several previous studies showing that obesity is associated with an increased
risk of aggressive disease (38-40). We are aware of the number of biases potentially contributing to
these discrepancies, primarily including the multiple biological links that certainly exist between
obesity, with its dramatic impact on the metabolism in general and on the metabolism of steroids
specifically, and PCa.
Our study is not devoid of limitations. The study reports the results of a sophisticated exploratory
analysis that may be optimal for this cohort of nonscreened, same-race patients but that would
deserve external validation with an independent sample and, possibly, with men from different
countries or ethnic backgrounds. A second limitation is that our study did not use gas
chromatography–mass spectrometry (41), which is considered the gold standard for measuring
circulating tT levels; in contrast, to reflect common practice of a clinical biochemistry laboratory,
we elected to measure circulating tT using commercially available analytic methods. A further
major limitation comes from the idea that endocrine biology of prostate tissue is dependent on the
exposure time at a given concentration of sex steroid, which, in turn, depends on serum fluctuations
during the lifespan of the individual. In this context, one may speculate that a single serum
assessment might not adequately represent the prostate’s hormonal environment throughout the
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lifespan of each subject or at least for the duration of the malignant transformation and progression
toward higher aggressiveness. However, we consider it almost clinically impossible to follow the
circulating hormonal milieu of a sufficient number of men across their entire lives to assess the role
of sex steroids as independent predictors of the eventual biology of PCa. Our analyses did not even
consider the correlation between androgen concentrations in the circulation and actual
concentrations in the prostate (42). Although the lack of that assessment might be considered a
methodological flaw, it eventually exceeds the clinical applicability of biochemical parameters that
may be of interest as routinely available predictors of pathologic outcomes at RP.
As a final point, it is certainly of importance to emphasize that the study lacks a measurement of
either circulating or intraprostatic dihydrotestosterone (DHT), the 5-reduced T product which
binds androgen receptors (ARs) with high affinity both at the normal and the prostate tumor tissue
level (43,44), eventually acting as a more active androgen than T (45). Overall, 5-reductase
inhibitors (5ARIs) reduce serum DHT, and dutasteride demonstrated to cut circulating DHT values
by at least 90% in men with localised PCa (46,47). Translationally, the two largest trials that
investigated the use of 5ARIs showed an overall relative reduction of 23 to 25% in PCa diagnoses,
with an absolute increase in the incidence of high-grade PCa in the chemoprevention group in both
trials (48,49). More recently, dutasteride demonstrated to significantly delay PCa progression as
compared with placebo (50), and these findings have supported the idea that using a 5ARI may
become of benefit to reduce the need for aggressive treatment in men undergoing active
surveillance for low-risk PCa (50). The absence of any DHT measurement makes it impossible to
obtain a correct and refined assessment of what might objectively be the role of the U-shaped
association described between circulating sex steroids and high-risk PCa in justifying how a
variation of the serum levels of these extremely active androgens may affect the prostatic cell
biology and the pathophysiological history of the prostate tissue itself. However, although further
studies are certainly needed, we could speculate that for the lowest tT and tT–E2 ratio values, DHT
hydrophobicity may strengthen human AR intermolecular interactions, slow the dissociation rate of
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bound androgen, and stabilize the ligand-bound AR (45); moreover, at the lowest androgen levels
DHT formation could be also secured and maintained by increased levels of 5a-reductase isoforms
present at higher levels in PCa but less expressed in normal human physiology (45). Conversely, it
emerges paradoxically more difficult to explain the correlation between the highest levels of sex
steroids (mainly tT) and high risk PCa since debating such a relationship by stressing that for high
values of those circulating hormones there is a greater substrate for 5-reductases, a greater
possibility of activation of the intraprostatic ARs, and subsequently a greater likelihood of high risk
Pca would certainly be too simplistic.
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CONCLUSIONS
Our data suggest that preoperative circulating tT and E2 levels and the tT–E2 ratio were associated
with high-risk PCa, stratified according to the NCCN practice guidelines, in a large, homogeneous
cohort of nonscreened, same-race men undergoing RP. The association between the serum sex
steroids and PCa aggressiveness depicted a nonlinear U-shaped behavior (ie, both the lowest and
the highest circulating levels of sex steroids resulted significantly associated with high-risk PCa).
Patient age shows an overall trend toward significance. Conversely, these data showed that both
BMI and SHBG levels are not multivariate predictors of high-risk PCa. Further studies are needed
to more comprehensively understand the complex biology of the endocrine network in promoting
different facets of PCa.
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ACKNOWLEDGMENTS
The authors thank Dragonfly Editorial for reviewing the language in this manuscript.
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FIGURES LEGEND
Fig. 1a-1c
Figure 1a-1c depict the relationship between serum tT levels (ng/ml), E2 levels (pg/ml), and tT–E2
values and high-risk PCa at RP, respectively. [Y axis represents the risk (logarithmic scale) of high
risk PCa at RP]. In this context, high-risk PCa was significantly more frequent both for the lowest
and the highest circulating levels of serum tT and E2 (all p 0.03), depicting a nonlinear U-shaped
risk behavior (Fig. 1a and 1b). Similar behavior was observed for the relationship between tT–E2
values and high-risk PCa (all p < 0.001) (Fig. 1c).
Fig. 1d
Figure 1d depicts the relationship between serum SHBG levels (nmol/l) and high-risk PCa at RP.
[Y axis represents the risk (logarithmic scale) of high risk PCa at RP].
Fig. 2
Figure 2 depicts the relationship between patients age (years) and high-risk PCa at RP.
[Y axis represents the risk (logarithmic scale) of high risk PCa at RP]
Fig. 3
Figure 3 depicts the relationship between BMI values (kg/m2) and high-risk PCa at RP.
[Y axis represents the risk (logarithmic scale) of high risk PCa at RP]
Keys: tT = total testosterone; E2 = 17β estradiol; tT–E2 = total testosterone17β–estradiol ratio; BMI
= body mass index; SHBG = sex hormone binding globulin
24
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Table 1 – Patients’ characteristics and descriptive statistics
No. of patients
724
Age (years)
Mean (median)
64.4 (64.8)
Range
41.4 – 82.3
10th; 90th percentile values
54.7; 73.8
BMI (kg/m2)
Mean (median)
26.2 (26.0)
Range
17.3 – 41.2
10th; 90th percentile values
22.6; 29.9
PSA (ng/mL)
Mean (median)
11.7 (6.8)
Range
0.4 – 150.0
Clinical stage [No. (%)]
T1c
432 (59.7)
T2
212 (29.3)
T3
80
(11.0)
Biopsy Gleason sum [No. (%)]
6
442 (61.0)
7
211 (29.1)
8
71
(9.8)
Pathological stage [No. (%)]
pT2
523 (72.2)
pT3
195 (26.9)
pT4
6 (0.8)
Pathological Gleason sum [No. (%)]
6
280 (38.7)
7
343 (47.4)
8
101 (14.0)
tT (ng/mL)
Mean (median)
4.3
(4.3)
Range
0.02 – 13.6
10th; 90th percentile values
1.4; 6.9
tT 3 ng/mL [No. (%)]
177 (24.4)
E2 (pg/mL)
Mean (median)
33.1 (32.0)
Range
6.0 – 89.1
10th; 90th percentile values
18.5; 49.2
tT/E2 ratio
Mean (median)
0.1
(0.1)
Range
0.0 – 0.6
0.06; 0.10
10th; 90th percentile values
SHBG (nmol/L)
Mean (median)
36.7 (34.0)
Range
6.0 – 132.0
10th; 90th percentile values
21.0; 56.0
Keys: BMI = body mass index; PSA = prostate specific antigen; tT = total testosterone; E2 = 17β
estradiol; tT/E2 = total testosterone/17β estradiol ratio; SHBG = sex hormone binding globulin
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63.5 (63.5)
50.6 – 80.0
26.2 (26.1)
20.0 – 40.1
4.4 (4.2)
0.0 – 10.6
46 (18.3)
33.0 (32.0)
1.0 – 71.0
0.14 (0.14)
0.01 – 0.5
35.0 (34.0)
6.0 – 106.0
Age [years; mean (median)]
Range
BMI [kg/m2; mean (median)]
Range
tT [ng/mL; mean (median)]
Range
tT <3ng/mL [No. (%)]
E2 [pg/mL; mean (median)]
Range
tT/E2 ratio [mean (median)]
Range
SHBG [nmol/L; mean (median)]
Range
64.4 (64.8)
41.4 – 82.3
26.3 (26.0)
19.5 – 39.4
4.5 (4.5)
0.0 – 13.0
70 (22.0)
34.3 (33.2)
8.0 – 89.1
0.13 (0.13)
0.0 – 0.6
37.0 (34.0)
7.0 – 115.0
318 (43.9)
Intermediate
68.5 (66.4)
44.8 – 82.0
26.0 (25.6)
17.3 – 41.2
3.9 (3.9)
0.0 – 13.6
61 (39.4)
30.5 (28.0)
3.0 – 77.0
0.12 (0.12)
0.0 – 0.3
39.0 (36.0)
11.0 – 132.0
155 (21.4)
High
0.09
0.69
0.023
<0.001
0.008
0.005
0.69
0.37
3.78
(2, 24.76)
4.85
5.35
2.22
p – value
4.7
F
Keys: BMI = body mass index; tT = total testosterone; E2 = 17β estradiol; tT/E2 = total testosterone/17β estradiol ratio; SHBG = sex hormone
binding globulin
p value according to ANOVA or 2 test, as indicated.
251 (34.7)
Patients [No. (%)]
*
Risk classes
Low
Variable
Table 2 – Patients’ characteristics and descriptive statistics according to NCCN guidelines™ risk classes after definitive therapy
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[0.96 - 1.00]
1.01; 0.84
[0.95 - 1.06]
--; <0.001
[0.96 - 1.00]
1.00; 1.00
[0.95 - 1.05]
--; <0.001
--; 0.05
--; 0.69
--; 0.002
--; 0.04
[1.29 – 1.98]
[1.62 – 2.30]
[0.80 - 1.19]
[0.78 - 1.07]
--; 0.005
[0.47 - 0.77]
[0.45 - 0.69]
--; 0.006
1.60; <0.001
vs.
[0.98 - 1.05]
[0.95 - 1.01]
[0.90 - 1.06]
1.03; 0.15
1.00; 0.66
[0.99 – 1.02]
[1.00 – 1.02]
1.01; 0.15
Restricted cubic spline functions with three knots tested the potential nonlinear association between predictors and NCCN guidelines PCa risk classes. Two models were developed: Model 1 included age, BMI, and
continuously coded tT, E2, and SHBG levels; Model 2 included age, BMI, and tT–E2 ratio values.
[1.00 – 1.02]
1.01; 0.07
[0.94 - 1.02]
[0.92 - 0.99]
1.03; 0.13
0.97; 0.12
0.98; 0.41
0.96; 0.05
1.02; 0.29
[1.10 – 1.24]
[0.95 - 1.01]
1.17; <0.001
[1.10 – 1.24]
[0.47 - 1.85]
[0.49 -3.94]
[0.52 - 1.29]
[1.26 -2.41]
percentile
[0.80 – 0.90]
0.85; <0.001
1.17; <0.001
[0.80 – 0.90]
0.85; <0.001
0.81; 0.01
[0.68 - 1.15]
1.55; 0.02
0.91; 0.24
10th
[1.13 - 3.69]
1.15; 0.07
0.85; 0.04
vs.
[1.10 - 1.33]
1.27; 0.003
1.30; 0.02
1.00; 0.001
--; <0.001
[0.91 – 1.02]
90th
vs.
--; <0.001
[1.02 – 1.12]
--; 0.12
[1.10 - 1.17]
[0.92 - 1.00]
[0.93 - 0.99]
--; 0.003
1.07; 0.005
1.13; <0.001
0.96; 0.05
0.96; 0.02
[0.94 - 1.03]
[0.90 – 0.98]
0.94; 0.002
--; 0.008
0.98; 0.43
[0.87 – 0.92]
0.90; <0.001
[0.90 - 0.97]
[1.01 - 1.08]
1.05; 0.02
0.93; 0.001
[1.02 - 1.08]
1.05; 0.002
[0.99 - 1.05]
0.96; 0.23
[0.88 - 4.37]
th
10
[0.97 - 1.05]
1.01; 0.59
--; <0.001
Model 2
1.03; 0.06
10th percentile
>10 -<90
th
percentile
90
th
[1.02 - 1.09]
10th percentile
th
1.05; 0.002
>10th-<90th vs.
percentile
[0.52 – 0.80]
1.93; <0.001
0.98; 0.81
0.91; 0.24
[0.44 – 0.62]
0.60; <0.001
10th
[0.85 - 1.27]
0.56; <0.001
vs.
[0.99 - 1.34]
90th
[1.25 - 2.01]
0.64; <0.001
--; <0.001
[0.91 – 1.03]
0.97; 0.29
[1.00 – 1.06]
1.03; 0.03
Model 1
MVA models
[1.37 - 2.04]
0.52; <0.001
--; <0.001
[0.92 – 1.03]
0.98; 0.43
[1.01 – 1.06]
1.04; 0.006
UVA model
10th percentile
1.04; 0.68
--; 0.89
1.15; 0.07
--; 0.12
[0.43 - 1.07]
1.02; 0.47
[0.79 - 1.02]
1.00; 0.99
Model 2
1.67; <0.001
[0.97 - 1.07]
1.01; 0.54
[0.98 - 1.02]
1.00; 0.96
Model 1
MVA models
[0.97 - 1.06]
1.02; 0.51
[0.98 - 1.02]
0.99; 0.92
UVA model
High risk
>10th-<90th vs.
1.59; <0.001
[0.57 1.64]
1.01; 0.69
[0.96 - 1.00]
0.98; 0.11
Model 2
risk
Intermediate
Keys: BMI = body mass index; tT = total testosterone; E2 = 17β estradiol; tT/E2 = total testosterone/17β estradiol ratio; SHBG = sex hormone binding globulin
SHBG
ratio
tT/E2
E2
tT
BMI
0.98; 0.08
0.98; 0.02
Model 1
Age
MVA models
UVA model
Predictor
Low risk
Table 3 – Univariate (UVA) and multivariate (MVA) logistic regression analyses with restricted cubic spline functions with three knots predicting low, intermediate and high risk class PCa (OR; p – value [95%CI]) among
the whole cohort of patients.
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SERUM SEX STEROIDS DEPICT A NONLINEAR U-SHAPED
ASSOCIATION WITH HIGH-RISK PROSTATE CANCER AT
RADICAL PROSTATECTOMY
Andrea Salonia, Firas Abdollah, Umberto Capitanio, et al.
Clin Cancer Res Published OnlineFirst May 15, 2012.
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