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androgen-mediated transcriptional activity in the prostate
when applied in combination with the androgen .
Another possible mechanism linking smoking and
aggressive PCa involves changes in the sex steroid pathway.
Current smokers have higher concentrations of total
testosterone, free testosterone, total estradiol, and free
estradiol than former or never smokers . Smoking may
alter testosterone secretion from Leydig cells or may act as
an aromatase inhibitor, reducing the conversion of testos-
terone to estradiol, thus increasing testosterone concentra-
tions . Data from the Third National Health and
Nutrition Examination Survey (NHANES III) also showed
that higher daily numbers of cigarettes smoked, pack-years
smoked, and serum cotinine were all associated with
greater concentrations of total and free estradiol. Smoking is
associated with increased estrogen 2-hydroxylation in
the liver, causing the formation of 2-hydroxy estrogens
. Although the exact role of androgens and estrogens in
PCa development and progression is still unclear, it has been
suggested from animal and experimental studies that
testosterone may exert a differentiating effect on PCa and
that elevated estrogen levels may promote testosterone-
induced carcinogenesis and result in higher-volume and
more aggressive PCa .
Another possible mechanism relates to inflammation.
Smoking induces inflammation in various tissues , and
smokers have more inflammation within the prostate than
nonsmokers Chronic prostatic inflammation as ob-
served in smokers is associated with a milieu rich in
proinflammatory cytokines, inflammatory mediators, and
growth factors that may lead to an uncontrolled prolifer-
ative response with rapidly dividing cells that are more
likely to undergo mutation, as observed in cancer .
Although not heretofore studied in the prostate, nicotine
can also induce angiogenesis in some tissues, and smoking
can inhibit a wide variety of immune reactions including
response to vaccines. Both conditions may lead to faster
cancer progression and worse prognosis for smokers .
Possible biological mechanisms linking smoking with
PCa development are summarized in .
3.2.2. Clinical evidence
Despite the links between smoking and a variety of solid
tumors as well as the multitude of potential biological
pathways affected by smoking that are involved in PCa
carcinogenesis, the association between cigarette smoking
and PCa remains a matter of debate . Recently,
two meta-analyses summarized the evidence regarding
the association between cigarette smoking and PCa risk
. Ameta-analysis of 24 prospective studies published
in 2010, but including studies up to February 2007, found no
significant association between current smoking and PCa
Table 1 (Continued )
Study Study name
(or description);
country, recruitment
period
Study
design,
outcome
Last FU
(F r)
Total no. men;
cases
Smoking
categor
No. of
case
RR (95% CI
Heikkila et al,
2013
IPD-Work Consortium;
Europe, 1985–2002
Cohort,
incidence
2008 (12) 116 056; 865 Nonsmoker
Current
706
159
Referent
0.70 (0.59–0.84) d
Koutros et al,
2013
Prostate, Lung,
Colorectal and Ovarian
Cancer Screening Trial
(PLCO); USA,
1993–2001
Nested
CCS,
incidence
2009 (3.4) 28 243; 680 (824) Never-smoker
Ever
Current
247
46
381
Referent
0.70 (0.58–0.84)d
0.50 (0.36–0.69) d
Lemogne et al,
2013
GAZEL study; France,
1989
Cohort,
incidence
2009 (15.2) 8877; 412 Never-smoker
Ever
NR
NR
Referent
0.86 (0.73–1.00)
Onitilo et al, 2013 Marshfield Clinic; USA,
1995–2009
Cohort,
incidence
2011 (NR) 33 832; 3432 Before DM onset
Never-smoker
Ever
After DM onset
Never-smoker
Ever
NR
NR
NR
NR
Referent
0.92 (0.85–1.18)
Referent
0.83 (0.74–0.94)
Rohrmann et al,
2013
European Prospective
Investigation into
Cancer and Nutrition
(EPIC); Europe,
1992–2000
Cohort,
incidence
2009 (11.9) 145 112; 4623 Never-smoker
Ever
Current
1547
3076
1080
Referent
0.93 (0.89–0.98)
0.90 (0.83–0.97)
Cohort,
mortality
2009 (11.9) 145 112; 432 Never-smoker
Ever
Current
128
304
121
Referent
1.06 (0.87–1.24)
1.27 (0.98–1.65)
Sawada et al,
2013
Japan Public Health
Center-based
Prospective Study
(JPHC); Japan, 1990–NR
Cohort,
incidence
2010 (16) 482 018; 913 Never-smoker
Ever
Current
(cumulative use)
257
647
380
Referent
0.80 (0.72–0.89)
0.79 (0.68–0.89)
CI = confidence interval; CCS = case-control study; DM = diabetes mellitus; FU = follow-up; NR = not reported; RR = risk ratio.
Adapted from Islami et al .
* Data on cigarette smoking. For qualitative measures of use, data on current cigarette smoking (at baseline) are shown in this table.
a The mean or median of follow-up in years.
b The numbers in parentheses are the number of controls in nested CCSs.
c Cumulative use during previous decade.
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